TW200413379A - Fused azole-pyrimidine derivatives - Google Patents

Abstract

The present invention relates to novel fused azolepyrimidine derivatives, processes for preparing them and pharmaceutical preparations containing them. The fused azolepyrimidine derivatives of the present invention exhibit enhanced potency for phosphotidylinositol-3-kinase (PI3K) inhibition, especially for PI3K-γ inhibition and can be used for the prophylaxis and treatment of diseases associated with PI3K and particularly with PI3K-γ activity. More specifically, the azole derivatives of the present invention are useful for treatment and prophylaxis of diseases as follows: inflammatory and immuno-regulatory disorders, such as asthma, atopic dermatitis, rhinitis, allergic diseases, chronic obstructive pulmonary disease (COPD), septic shock, joint diseases, auto-immune pathologies such as rheumatoid arthritis, and Graves' disease, cancer, myo-cardial contractility disorders, heart failure, thromboembolism, ischemia, and atherosclerosis. The compounds of the present invention are also useful for pulmonary hypertension, renal failure, cardiac hypertrophy, as well as neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, diabetes and focal ischemia, since the diseases also relate to PI3K activity in a human or animal subject.

Description

200413379 A7

Technical ϋ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The potentiating potency of phosphoinositide-3-kinase (ΡΙ3Κ) inhibition, especially in the inhibition of ΡΙ3Κ-7, can be used to prevent and treat diseases associated with ρΙ3Κ, especially 疋ΡΙ3Κ·τ activity. More specifically, the azole derivatives of the present invention are useful for the treatment and prevention of the following diseases: inflammation and immune regulation disorders such as asthma, atopic skin, rhinitis, allergic diseases, chronic obstructive pulmonary disease (COPD): , shock, joint disease, spontaneous immunopathology such as rheumatoid arthritis, thrift, and Graves' disease, cancer, myocardial systolic dysfunction, heart failure, thromboembolism, ischemia, and atherosclerosis. The compounds of the invention may also be used in pulmonary or arterial blood pressure, renal failure, cardiac hypertrophy, and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, diabetes, and localized ischemia in human or animal subjects. Because these diseases are also related to PI3K activity. In inflammatory diseases, signal transduction pathways derived from chemoattractant receptors are considered to be important targets for controlling leukocyte motility, which is chemically attracted by activated heterotrimeric G-protein coupled receptors (GPCRs). Factor-controlled and thus triggering complex and diverse downstream intracellular events, signal transduction in one of the pathways, which leads to intracellular free Ca2+ activity, cell scaffold reorganization and direction shift, is determined by phosphoinosine 3-kinase (PI3K) Actively produced lipid-derived second messenger [ι, 2]. This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) ·; 4 words 1" ά ·; 10152025 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 200413379 A7 B7 V. Invention description service shiba acidification (four) grease Phytic acid inositol-4,5-di-hydroperate (PtdIns(4,5)P2k D3, basal position to obtain acid inositol J ^ scallate (Ptd (tetra) 3, 4, he), according to matrix specificity And protein knots/structures, and G include a class [4-6], which has a special value of 5 疋I^PI3Ks in leukocyte movement, all of which involve receptor-induced inflammatory cell responses and are subdivided into para-type ΙΑ ( Ρ11〇α, stone, r) steroidal enzymes (ρ110α, CAM, 5) combine with the $ conjugated secondary material containing two SH2 regions to form a heterodimeric complex that recognizes phosphoric acid The tyrosine YxxM element, which results in binding to the receptor tyrosine kinase and subsequent activation via the receptor tyrosine kinase [^], is considered to be associated with cell proliferation and cancer, and IA accessory binding to activation. Rat oncogene, which is found in many cancers, expresses its enzymatic activity, and also finds p 110 α and /3 in humans Cancer plays an important role in growth [3]. 15 ΙΒ (ρ11〇^) enzyme, its expression is mostly confined to white blood cells, is activated by G protein / 3 r complex, and the role of the seven downstream membrane chemical attraction [7-9], pl〇l adapter protein, which is not similar to any other known white matter, is the element of pi 1〇γ (PI3K γ ) response to G protein [10-12]. Recently, in the study of mice lacking functional Pi3Kr (PI3Ky_8 mice), which is viable, reproducible and normal life in traditional mouse devices, it is revealed that when using GPCR stimulators such as ship lp, When stimulated by C5a or IL-8, neutrophils are unable to produce PtdIns(3,4,5)P3, which proves that in these cells PI3K τ is the only -4- of this paper size that is coupled to these GPCRs. CNS)A4 specification (210x297 mm) installed tj Green Ministry of Intellectual Property Intellectual Property Officer X Consumer Cooperation 钍 Printed 200413379 A7 B7 V. Invention Description (3 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed PI3K [13-16], and In these neutrophils, there is also no protein kinase Β (ΡΚΒ) PtdIns ( 3,4,5) iV-related activation, while ρκβ can still be activated by GM-CSF or IgG/C3b-coated granules via ρ11〇α, CAM or 5, while G-protein-intermediate response, for example pLC recalls intact, ΡΙ3Κγ-/- mice develop damaged thymocyte development and increase the number of neutrophils, monocytes and eosinophils [14], and neutrophils and giants isolated from ΡΙ3Κr mice The azole cells show severe defects in the response to GPCR-stimulated swords and chemotactic agents' movements and respiratory bursts [14,16], transgenic mice expressing green fluorescent protein (GFP) under the control of endogenous PI3Kr promoters. The expression of PI3Kr was also examined, and GFP was detected in spleen and bone marrow cells and neutrophils. It is suggested that the expression of pi3K is limited to hematopoietic cells. On the whole, ΙΒ_酸肌菩U enzyme H3Kr seems to be The development of the control of white blood cell flow and the development of homo-selective inhibitors of ρΐ3κ^ must be a valuable anti-inflammatory strategy. Hypertrophic responses can be triggered by the ΡΙ3Κ communication pathway, and new studies published today confirm that the PTEN+PI3Kr pathway regulates myocardial contraction, whereas ΡΙ3Κα mediated changes in cell size during heart hypertrophy until heart failure, PI3Kr County rabbit + r疋As a negative adjustment of the heart contraction 20 agents. PTEN is a dual-specific protein-enzyme that was recently implicated in the cell growth signaling as Wei-inosine Wei_, and the tumor suppressor PTEN appeared to be acid-filled succinate inositol 3,4,5·three-disc. It is an important two-product produced by the action of PI3K. 5 10 paper scales are applicable to China National Standard (CNS) A4 regulations (21〇χ 297 mm loading 200413379 Α7 Β7 5' statement (4) PTEN reduced PIP3 content in cells and antagonized cell signaling by PI3K. It was also reported that expression of dominant negative PTEN resulted in hypertrophy of rat cardiac cardiomyocytes in tissue culture. PI3Kr regulates baseline cAMP levels in cells and controls Contraction, 5 This study also indicates that changing baseline cAMP levels leads to increased contraction in mutant mice [17]. Therefore, the results of this study show that PI3K τ is involved in myocardial contraction and therefore the inhibitor may be used to treat congestive heart failure, local deficiency Gray, pulmonary hypertension, renal failure, cardiac hypertrophy, atherosclerosis 10, thromboembolism, and diabetes. A PI3K inhibitor that is expected to prevent transmission from GPCRs and more The activation of immune cells should have a wide range of anti-inflammatory effects for the treatment of inflammation and immune dysregulation [2], including asthma, atopic dermatitis, rhinitis, allergic diseases, chronic obstructive pulmonary disease 15 (C0PD), defeat Hemorrhagic shock, joint disease, spontaneous immunopathology such as rheumatoid arthritis, and Graves' disease, diabetes, cancer, myocardial systolic dysfunction, thromboembolism [18], and atherosclerosis. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative Part of the PI3-kinase inhibitor was identified: Waterman, a mycotoxin originally isolated from Penicillium manotae [19], closely related but less than 20 incompletely identified deoxylectin And LY294002, which is a broad-acting kinase inhibitor quercetin-based derivative of quercetin [2〇]. US 3644354 discloses a 5-substituted 2-, 3-di-rat-like stagnation represented by the following formula [1,2-c] °Qui σ sit. Lin: -6- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description R'

R wherein R and RG are independently hydrogen, lower alkyl, lower alkenyl; R' and R" are independently hydrogen, halo, lower alkyl, lower alkoxy, or

• 11丨 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed Clothes 15 As a hypotensive agent and coronary artery dilator. However, none of these references disclose fused azopyrimidines, such as, but not limited to, 嗤-σ 奎哇, 嗤-吼σ定基 密, and saliva-α. The dense σ set, the σ sit- shout σ fixed base tower 17 well, the 嗤-, the 唆 base three σ well, the 嗤-° set bite, the 嗤-, the σ fixed base four σ well and the fused. Sitting at the 5 or 6 position of the other thiolated 20 amine or -CR5R6-C(〇)- (R5 is hydrogen or Cw alkyl and R6 is halo, hydrogen or Cu alkyl) linkage and Other derivatives having PI3K inhibitor activity. There is still a need to develop compounds that can be used to treat and prevent inflammation, cancer, and/or myocardial contractility associated with PI3K activity. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200413379 A7 __ —_B7 V. Description of the invention (6) Summary of the invention The results of the intensive study on the chemical modification of the fused 4 (tetra) derivatives, The inventors of the present invention have found that compounds of the novel chemical structure associated with the present invention have TOK inhibitory activity and particularly have pDKr inhibitory activity, and 5 the present invention is completed based on these findings. The present invention provides a novel fused saliva of formula (I). Bite derivatives, tautomers and stereoisomers thereof, and salts thereof.

Wherein 15 X represents CR5R6 or NH; Y1 represents CR3 or N; the chemical bond between Y2 and Y3 represents a single bond or a double bond, provided that when Υ2Υ3 represents a double bond, the Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative prints Υ And γ3 independently represents CR4 or Ν, and 20 when γ2-Υ3 represents a single bond, Υ2 and Υ3 independently represent CR3R4 or NR4; z, Z2, Z3 and z4 independently represent ch, CR2 or N; R represents as needed An aryl group having 1 to 3 substituents selected from R11, optionally a C3_8 cycloalkyl group having 1 to 3 substituents selected from R", a paper size fee standard ^^7Ι10χ297 public hair) 200413379 A7 B7 V. Description of the invention (7) Cw alkyl group substituted with an aryl group, a heteroaryl group, a cN6 alkoxyaryl group, an aryloxy group, a heteroaryloxy group or one or more halogen groups, if necessary, via a carboxyl group , aryl, heteroaryl, Cw alkoxyaryl, aryloxy, heteroaryloxy or one or more substituted Ci-6 alkoxy-5, or 3 to 15 membered mono- or di-cyclic saturated or Unsaturated and containing 1 to 3 heteroatoms selected from the group consisting of N, anthracene and S, and optionally 1 to 3 substituents selected from R11, wherein R11 represents halogen , nitro, hydroxy, cyano, carboxy, amine, Ν-(<^_6 alkyl)amine, N-(hydroxy Cw alkyl)amine, N,N-di(C^alkyl)amine Base, NJCu fluorenyl), N-(indenyl)-N-(Cualkyl)amine, NJCu alkylsulfonyl)amine, N-(carboxyl 15 Ci-6alkyl)-N -(Ci_6 alkyl) amine group, N-(Ci_6 burning S) base, Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative, printing base, N-[N,N-di(Ci-6 alkyl) aminide Amino group, N-[N,N-di(Cualkyl)amino (Cw alkyl)methylene]amino group, N-[N,N-di(Ci_6 alkyl)amino C2_6 alkenyl Amino, aminocarbonyl, Ν-((^-6 alkyl)aminocarbonyl, N,N-di(Cualkyl)aminocarbonyl 20, 〇3-8 cycloalkyl, Cu alkylthio, cumane a sulfonyl group, an amine sulfonyl group, a Ci_6 alkyl ester group, an N-arylamine group, wherein the aryl moiety is optionally substituted with 1 to 3 substituents selected from R1g1, N-(aryl Ci -6 burning Amino group wherein the aryl moiety is optionally substituted with 1 to 3 substituents selected from R1()1, an arylalkyl ester group wherein the aryl moiety is of the Chinese National Standard (CNS) A4 specification ( 210 X 297 200413379 A7 B7 V. INSTRUCTIONS (8) Parts are 1 to 3 substituents selected from R1()1 as needed, optionally via a mono-, di- or di-halo group, an amine group, N-( Ci-6 alkyl) Alkyl or N,N-di(Cw alkyl)amino substituted Cw alkyl, via mono-, di- or di-halo, N-(C 1-6 alkyl) a yellow-branched amino group or an N-5 (aryl)-hydrocarbyl-substituted Ci_6 alkoxy group, or 5 to 7 members which are saturated or unsaturated and contain 1 to 3 hetero atoms selected from the group consisting of 0, S and N. a ring containing 1 to 3 substituents selected from R1 (}1, 10 wherein R1()1 represents a ii group, a carboxyl group, an amine group, an alkyl group), an N,N-di(Cw alkyl group), if necessary Amino, aminocarbonyl, fluorenyl-((6-alkyl)aminocarbonyl, anthracene, fluorenyl-di(Cw alkyl)aminocarbonyl, pyridyl, optionally via gas group or early _, di- or two · Ci-substituted Ci _6 burned 15 base, or printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative as needed. Cyano, carboxyl, amine, Ν-((^_6 alkyl)amine, N,N- (Ci_6 alkyl)amino, aminocarbonyl, N-(CN6 alkyl)aminocarbonyl, N,N-di(Cw alkyl)aminocarbonyl, or mono-, di- 20 di-dentate substituted Ci alkoxy, R2 represents hydroxy, halo, nitro, cyano, amine, NJCw alkyl) amine, N,N-di(Cm alkyl)amine, N- (hydroxy Cw alkyl) amine group, N-(hydroxy Cw alkylalkyl) amine group, CN6 decyloxy group, amine Cw decyloxy group, C2_6 alkenyl group, aryl group, 5 to 7 members -10- paper The scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention (9) Saturated or unsaturated and contains 1 to 3 heteroatoms selected from strontium, S&N and optionally Hydroxy, Ci_6 alkyl, Ci-6 alkoxy, keto, amine, amino Cw alkyl, n_(Ci_6 alkyl)amine, N,N-di(CN6 alkyl)amine, team ((^6) Amidino, NJCu 5 alkyl)carbonylamino, phenyl, phenyl Cw alkyl, carboxy, CN6 carbyl, amine phenyl, alkyl)aminocarbonyl or N,N-(Cl_6) a heterocyclic ring of an amine substituent, -C(0)-R20 wherein ίο r2G represents an alkyl group, a Cu alkoxy group, an amine group, an N-(Cl 6 alkyl)amino group, N,N-di ( Cw alkyl)amino, ν-((6 yl)amino, or 5 to 7 members saturated or unsaturated and containing 1 to 3 From heteroatoms including 0, S and N and optionally via Cl_6 alkyl, Cw alkoxy, keto, amine, N-(Ci6 alkyl) 15 amine, N,N-di(Cw alkyl) Amino, Ν-(<^6醯)-amino, phenyl or octyl-substituted heterocyclic ring, optionally substituted with a C21 alkyl group, or printed by the Intellectual Property Office of the Ministry of Economic Affairs R21 substituted Ck alkoxy, 20 wherein R21 represents cyano, mono-, di- or tri-halo, trans, amine, Ν-β fluorenyl) amine, N,N-di(cN6 alkyl Amino, N-(hydroxy Cw alkyl)amino, N-(-phenylphenyl 6 alkyl)amine, amine Cwalkenyl, Cw alkoxy, hydroxyCl-6 alkene-11- paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 A7 B7 V. INSTRUCTIONS (10) Oxyl, -C(0)-R2G1, -NHCXOH^i, c3_8 cycloalkyl, isoindole Base, oxime imine, 2-keto sigma, aryl or 5 or 6 members saturated or unsaturated and contain! Up to 4 heteroatoms selected from the group consisting of 0, S and fluorene, and optionally, a 5-, a C 1-6 alkyl group, a Cw alkoxy group, a Cb6 group, a ketone group, an alkoxy group, a ketone group, Amine, amine c16 alkyl, N-(C-6 alkyl) amine, N,N-di(C1-6 alkyl)amine, N-(C!-6)amino or octyl a heterocyclic ring substituted, wherein 10 R2i)1 represents a hydroxyl group, an amine group, an NJCw alkyl group amine group, an N,N-di(Cw alkyl)amino group, and an N-(halophenylCi-6 alkyl)amine a group, a Ck alkyl group, an amine group Ci_6 alkyl group, an amine group C2-6 group, a Ci alkoxy group, a 5 or 6 member saturated or unsaturated, and having 1 to 4 hetero atoms selected from the group consisting of ruthenium, S and N. And, if desired, 15 via hydroxyl, Cw alkyl, Cw alkoxy, Cw alkyl ester, rosinyl Ci-6 alkoxy, keto, amine, N-(Ci-6 alkyl)amine, N,N-di (Cw alkyl)amino, NO^-6 fluorenyl) or benzyl substituted heterocyclic ring; printed by the Intellectual Property Office of the Ministry of Economic Affairs

R stands for hydrogen,! An i group, an amino group, or a Ci_6 alkyl group substituted with an aryl G i, 6 20 alkoxy group or an early-, di- or tri-halogen group; R 4 represents hydrogen or CU 6 alkyl; W represents hydrogen Or Cu alkyl; and R0 represents halo, hydrogen or CU6. The compound of the present invention exhibits PI3K inhibitory activity and PI3K-r inhibits live-12- This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 public) 200413379 A7 B7 V. Invention Description (11) Sex, which is therefore suitable for use Manufacture of pharmaceutical or pharmaceutical compositions for the treatment and prevention of PI3K and/or PI3K-T related diseases such as inflammation and immunomodulatory disorders such as asthma, atopic dermatitis, rhinitis, allergic diseases, chronic obstructive pulmonary disease ( COPD), septic shock, joint 5 disease, spontaneous immunopathology such as rheumatoid arthritis, and Graves' disease, myocardial systolic dysfunction, heart failure, thromboembolism, ischemia, cardiac hypertrophy, atherosclerosis and Cancers such as skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, stomach cancer, brain tumor, blood cancer, and the like. 10 The compounds of the invention may also be used in the treatment of pulmonary hypertension, renal failure, Huntington's disease and cardiac hypertrophy, and neurodegenerative disorders such as Parkinson's disease, Alzheimer's, in human or animal subjects. Symptoms, diabetes, and localized ischemia, as these diseases are also associated with PI3K activity. 15 The present invention also provides a method for treating a disorder or disease associated with PI3K activity in a human or animal subject for treatment or the Ministry of Economic Intelligence, an employee's consumer cooperative, including the effective medical amount in formula (I) The fused azole pyrimidine derivative, its tautomeric and stereoisomeric forms, or a physiologically acceptable salt thereof, is administered to the subject. The present invention also provides the use of a fused azole pyrimidine derivative, a tautomer and a stereoisomeric form thereof, or a physiologically acceptable salt thereof, for the preparation of a medicament represented by the formula (I). In a specific embodiment, the present invention provides a fused azole pyrimidine derivative of the formula (I), a tautomeric form thereof, and a stereoisomer form thereof, or a-13-paper scale applicable to the Chinese National Standard (CNS) )A4 size (210x297 mm) Α7

200413379 Physiologically acceptable salt; wherein X represents CR5R6 or NH; Y1 represents CR3 or N; the chemical bond between 5 YY represents a single bond or a double bond, provided that when Y2 two Y3 represents a double bond, Y2 and Y3 independently Representing ^^ or Han, and when y2-Y3 represents a single bond, Υ2&γ3 independently represents 4 or NR4; 10 Ζ, Ζ2, Ζ3, and Ζ4 independently represent CH, CR2 or Ν; R1 represents on-demand order a di- or tri-, phenyl, methoxyphenyl, phenoxy or thiol-substituted Ci-6 alkyl group, optionally having a mono-, di- or tri--yl group, a phenyl group, a methoxyphenyl, phenoxy or thiol-substituted Cl-6 alkoxy group, 15 or one of which is selected from the group consisting of a carbocyclic or heterocyclic ring, a cyclopropyl group, a cyclohexyl group, a hexahydropyridinyl group, or a Hydropyridyl, pyridinyl, alpha ratio. Sedentyl, furyl, thiol, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, isoimidazolyl, pyrazolyl, 20 丨, 2,3 thiadiazolyl, 1 , 2,4-thiadiazolyl, iota, 2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, anthracene, 2,4-anthracene Diazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, anthracene, 2,3-triazolyl, 1,2,5-trisal, 1,3, 4-three. Sit, phenyl, σ thiol, π specific well, pyrimidinyl, morphine, 1-benzophenylthio, benzothiazole-14- This paper scale applies to China National Standard (CNS) A4 specification (210 Χ 297 mm)

Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed 200413379 A7 B7 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (13) Base, Benzimidazolyl, 3H-Imidazo[4,5-b]pyridyl Benzene tris-sine, fluorenyl, σ guji, sigma and [l,2-a]4b σ, quinolyl and 1,8-naphthyl, 5 of which are The heterocyclic ring is optionally selected from 1 to 3, including a hydroxyl group, a halogen group, a nitro group, a cyano group, a thio group, an amine group, an N-(Ci_6 alkyl)amino group, and an N,N-di(Ci-6 alkyl group). Amine, Ν-γκ醯)amino, N-(Ck alkyl)amino, Ν-(methylindenyl)-N-CCw alkyl)amine, N-[N,N-di(Cw Alkyl)aminoalkylidene]amino, N-[N,N-di10(Cualkyl)amino (Ci-6 alkyl) anthracene]amino, N-[N,N- Ci-6 alkyl)amino C2-6 dilute] amine group, Ci_6 thiol group, Ci-6 aryl group, amine continuation base, Ci_6 alkoxy group, Ci_6 alkyl ester group, σ thiol group Substituted with a substituent of a sulfhydryl group, a fluorenyl group, a fluorenyl group, an indolyl group, a phenyl Cu alkyl ester group, 15 a thiazolyl group substituted with a pyridyl group, a hexahydropyrylene group substituted with a Cu alkyl group or a Cu alkoxy group, and a Cl -6 alkyl group substituted with an early-, di- or di-halogen group, 20 R2 represents a rythyl group, a halogen group, and a fluorene group. Base, cyano group, thiol group, amine group, N-(Ci_6 alkyl)amino group, N-(hydroxy Cm alkyl)amino group, N,N-di(Ck alkyl)amino group, N-(hydroxyCN6 Alkylalkyl)amine, C2_6 alkenyl, Cn6 alkyl ester, aminocarbonyl, Cw methoxy, amino Cu methoxy, furyl, fenofyl, phenyl, hexahydropyridinium 15-

This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Inventive Note (14) Base, aryl, pyrrolidinyl group substituted by Cw mercaptoamine group, if necessary, via hydroxyl group a Cu alkyl group, a carboxyl group, an aminocarbonyl group, an N-(Cu alkyl)aminocarbonyl group or an N,N-di(CN6 alkyl)aminocarbonyl group, which is substituted with a hexahydroquinone sigma group, which is optionally calcined by Cu. a substituted hexahydropyridinyl group, optionally containing an aryl group, a mono-, di- or tri-halo group, a trans group, an amine group, an NKCw alkyl group, an N-(hydroxy Ci-6 alkyl)amine group, N,N-di(Ck alkyl)amino, C3_6 cycloalkyl, tetrazolyl, tetrahydropyran 10, morphine, quinone, 2-keto-1,3-anthracene An oxazolidinyl group, a phenyl substituted Ci_6 alkyl group, -C(0)-R201, a pyrrolidinyl group substituted with a Cu sulfhydryl group, if necessary, via a hydroxyl group, a Cw alkyl group, a carboxyl group, an aminocarbonyl group, N -15 (CN6 alkyl)aminocarbonyl or N,N-di(Cw alkyl)aminocarbonyl substituted hexahydro sulphate, or hexahydropyrryl substituted by Ci_6 alkyl, Ministry of Economics Property Bureau employee consumption cooperative printing Wherein 20 R2()1 represents a hydroxyl group, an amine group, an NJCu alkyl group), an N,N-di(C^alkyl)amino group, an N-(i-benzyl)amino group, a Cw alkyl group, a 6-alkane group. An oxy group, a tetrazolyl group, a tetrahydropyranyl group, a ruthenium group, a pyrrolidinyl group substituted with a Ci_6 mercapto group, if necessary, via a hydroxyl group, a CN6 alkyl group, a carboxyl group, an aminocarbonyl group, or N- 16- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (15) (C ^ alkyl) aminocarbonyl Or a hexahydro group substituted with an N,N-di(Cw alkyl)aminocarbonyl group.比 定 base, or hexanitroguanidine σ well base substituted by C 1 alkyl group, 5 depending on the need of gas base, mono-, di- or tri-based, per-base, Cl -6 alkoxy, hydroxy Cw alkoxy Base, amine group, n-(cN6 alkyl)amino group, N,N-di(Cu alkyl)amino group, pyrrolyl group, tetrazolyl group, tetrahydropyranyl group, morpholinyl group, quinone imine a 2-keto-1,3-oxazolidinyl group, a phenyl group, a -C(0)-R2G1 substituted Cu alkoxy group, 10 a pyrrolidinyl group substituted with a Cw decylamino group, if necessary, a hexahydrogen ratio sigma group substituted by a hydroxyl group, a Cw alkyl group, a carboxyl group, an aminocarbonyl group, an N-(Cu alkyl)aminocarbonyl group or an N,N-di(Cualkyl)aminocarbonyl group, or 15 as needed Six rats replaced by C1 _6 alkyl. Ratio 17 well, wherein R2G1 represents hydroxy, amine, NKCk alkyl) amine, hydrazine, fluorenyl-bis(Cu alkyl)amine, N-(i-benzylbenzyl)amine, Cw alkyl, 6-burn An oxy group, an amine group C2-6 alkenyl group, a tetras-s-sine group, a tetrahydropyranyl group, a 20 sulphonyl sulphate group, a pyrrolidinyl group substituted with a Ci_6 mercapto group, if necessary, Cl stomach 6-, pyrenyl, amino-based, N-(CU6 alkyl)aminocarbonyl or N,N-di(Cw alkyl)aminocarbonyl substituted hexahydropyridinyl, -17-benz The paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm)

200413379 A7 B7 V. INSTRUCTIONS (16) or hexahydropyrrole substituted by Ci_6 alkyl group as needed; R3 represents hydrogen, i group, optionally aminocarbonyl group, aryl CN6 alkane group or early _, two - or dihalo-substituted Ci -6 alkyl, 5 R4 represents hydrogen or Cu alkyl; R5 represents hydrogen or Cw alkyl; and R6 represents hydrogen, halo or Cl -6 alkyl. In another embodiment, the present invention provides a fused azole pyrimidine derivative of the formula (I), a tautomer thereof and a stereoisomeric form thereof, or 10 a physiologically acceptable salt thereof; wherein X represents CR5R6 or NH; Y1 represents N; Y2 and Y3 represent CR3R4; 15 Y2 and Y3 represent a single bond; Z4 represents CH; Z1, Z2 and Z3 independently represent N, CH or CR2; Ministry of Economic Affairs Intellectual Property Office employees Consumer cooperatives printed R1 represents cyclopropyl, cyclopentyl, cyclohexyl, 2-furyl, 3-furanyl, imidazolyl, pyrimidine, σ 荅, hexahydropyridinium, 20 1 , 2,3-thiadiazolyl, 1,3-benzothiazolyl, morphine, 3Η-imidazo[4,5-7] < pyridine, 111-port ratio substituted by Cw alkyl - 2 -yl, 1H-pyran-3-yl substituted by Cu alkyl group, if necessary, substituted by 1 or 2 CU6 alkyl pyrazole groups, optionally 1 or 2 -18- paper scale Applicable to China National Standard (CNS) A4 Specification (210x297 mm) 200413379 A7 B7 V. INSTRUCTIONS (17) CN6 alkyl substituted isosazolyl, substituted by chlorine, nitro, cyano or Cw alkyl as needed 2-Thienyl, 3-thienyl 5-substituted by chloro, nitro, cyano or Cu alkyl, optionally substituted with C! -6 alkyl or benzyl ester, hexahydropyridyl It is required to have 1 to 3 amine groups selected from the group consisting of fluorine, chlorine, hydroxyl, nitro, cyano, Wei, Ci_6 alkyl, Ci-6 alkoxy, Ci-6, amine, NJCw alkyl , NJCw fluorenyl)amino, N-10 (Ci-6 alkyl) amino, N,N-di(Ci-6 alkyl)amino, N-(methylindenyl)-NKCk alkyl)amine a phenyl group substituted with a substituent of a Cw alkylthio group, a Cw alkylsulfonyl group, an amine sulfonyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, and optionally a hexafluoropyrylene group substituted with a CK6 alkyl group, 15 Depending on the need, 1 or 2 selected from the group consisting of chlorine, hydroxyl, carboxyl, Cu, Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative, printing alkoxy, Cw alkylthio, amine, N-(Ci-6 alkyl)amine Base, N-(hydroxy Cualkyl)amino group, N,N-di(Cualkyl)amine group, N-(Cu醯)amino group, N-(Ci-6 alkyl)sulfonylamino group , N-[N,N-di(Cw alkyl)aminoindenyl]amine group and, if necessary, substituted by a trihalo group for 20 generations of C丨_6 alkyl group Substituting the 4-bite group, if necessary, a Cu-alkyl-substituted pyridinyl group, if necessary, 1 or 3, which is substituted with a group consisting of a CN6 alkyl group, a pyridyl group and an N-(Cw alkyl ester group) amine group. -thiazolyl, thiol substituted by C!_6 alkyl as required, -19- This paper scale applies to Chinese National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention (18) a benzopyridinyl group substituted with a cN6 alkyl group or a tri-i-yl cN6 alkyl group, a 1,2,3-benzotriazolyl group optionally substituted by a Cw alkyl group, optionally substituted with a trifunctional group as needed a C alkyl-substituted 5 1,8-naphthylpyridinyl group, optionally substituted by a tri-i, phenyl, phenoxy or thiol group, or optionally phenyl, phenoxy or thiophene a substituted cU6 alkoxy 10 group; R2 represents a fluorine, chlorine, > odor, a trans group, a nitro group, a vinyl group, a cyano group, an amine group, an amino ethoxy group, an NJCw alkyl group, an amine group, 6 alkyl)amino, N-(hydroxyCN6alkyl)-oxime-(<^_6 alkyl)amine, 2-butanyl, hexazone, fenofyl, phenyl, 15 Pyrrolidinyl substituted with acetaminophen, as appropriate The hexahydropyridyl group to be substituted by a hydroxy group, if necessary, a hexahydroquinone σ well base substituted with a mercapto group, a benzyl group, a 匕-6 alkyl ester group or an amine carbonyl group, printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative as needed Substituted by a gas group, a di-fluoro group, a thiol group, a methyl ester group, an amine group, a 20-butyl group, a tert-butyl ester group, a tetrahydropyranyl group or a ruthenium group

Cw alkyl, optionally via hydroxy, cyano, methoxy, methyl, tributyl, carboxyl, aminoethyl, dimethylamino, aminocarbonyl, methylaminocarbonyl, dioxime Aminocarbonyl, isopropylaminocarbonyl, fluorobenzyl-20- This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description ( 19) Aminomethyl, cyclopropyl, indoprozol sigma, hexahydro 0 to sigma, tetrahydro σ-pyranyl, ruthenium sulphate, ruthenium. a aryloxy group, a 2-keto-1,3-oxazolidinyl group, a quinone imine-fluorenyl group or a hydroxy Ci_6 alkenyloxy group substituted with Ci-6 alkoxy group, 5 R3 represents hydrogen; R4 represents hydrogen ; R5 represents hydrogen; and R6 represents hydrogen. In another embodiment, the present invention provides a fused 10 azole pyrimidine derivative of the formula (I), a tautomer thereof and a stereoisomeric form thereof, or a physiologically acceptable salt thereof; wherein X represents CR5R6 or NH; Y1 represents N; 15 Y2 and Y3 represent CR3R4; chemical bond between Y2=Y3 represents a single bond; Ζ3 and Ζ4 represent CH; Ζ1 and Ζ2 independently represent CH or CR2; R1 represents 3Η-imidazole[4 , 5-b]pyridyl, optionally substituted with a hydroxy group, an amine 20 group, an acetamino group, a methoxybenzyloxy group or a decylsulfonylamino group, or as needed 1,3-thiazolyl substituted with 1 or 2 thiol groups; R2 stands for fluorine, chlorine, bromine, fenofyl, hexahydropyrhyl, methyl hexa-21- This paper scale applies to Chinese national standards (CNS )A4 size (210 X 297 mm)

Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printing Socks 200413379 Α7 _____ Β7 V. Description of Invention (20) Hydroquinone, f-based, trifluoromethyl, or optionally via hydroxyl, cyano, carboxyl, dimethylamino a carbonyl group, a tetrahydropyranyl group, a phenanthroline group, a fluorenylcarbonyl group, a tetrazolyl group or a quinone imine group substituted Cl_6 alkoxy group, 5 R3 represents hydrogen; R4 represents hydrogen; R5 represents hydrogen; and R6 Represents hydrogen. In another embodiment, the present invention provides a fused oxazolyl derivative of the formula (1), a tautomer thereof and a stereoisomeric form thereof, or a physiologically acceptable salt thereof; wherein X represents CR5R6 Or NH; Y1 represents N; 15 Y2 and Y3 represent CR3R4; the chemical bond between γ2 and τγ3 represents a single bond; Z3 and Z4 represent CH; and z1 and Z2 independently represent CH or CR2. In another specific embodiment, the present invention provides a fused 20 scorpion bite derivative of the formula (1), a tautomer thereof, and a physiologically acceptable salt thereof; wherein 3 represents CR5R6 or NH ; Y1 stands for N;

This paper scale applies to the national standard (CNS) A4 specification (21〇χ297 mm) 200413379 A7

Y2 and Y3 represent cr3r4; the chemical bond between Y2 and Y3 represents a single bond; Ζ1 and Ζ4 represent CH; Ζ and Ζ3 independently represent CH or CR2. In another embodiment, the present invention provides a fused sit-like organism of the formula (1), a tautomer thereof and a stereoisomeric form thereof, or a physiologically acceptable salt thereof; wherein X represents CR5R6 or ΝΗ; ίο Y1 represents N; Y2 and Y3 represent CR3R4; the chemical bond between Y2 and Y3 represents a single bond; ζ1, Z3 and ζ4 represent CH; Z2 represents CR2. 15 Preferred compounds of the invention are as follows: N-(7,8--decyloxydihydro 17 m salido[l,2-c]. Kudzu sitting base) immortal amine; Ministry of Economics intellectual property Bureau employee consumption cooperative printed 2-(7,8-dimethoxy-2,3-dihydro-salt [l,2-c]. 奎 σ 林 -5 -5 - 吼 -3- -3- Diluted alcohol; 2〇Ν-(7,8-monodecyloxy-di-diazoxide misc and with ^-^ 口奎嗤口林巧-义) 1Η-benzimidazole-5-decylamine; 6 -(acetamido)-oxime-(7,8-dimethoxy-2,3-dihydroimidazo[nq咗嗤°L-5-yl) in the amine; N-{5-[ 2-(7,8-dioxaoxy-2,3-dihydro. rice bran [l,2-c] oxime. sitting mouth -23-

Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Cooperative, Printed 200413379 V. Invention Description) 1-hydroxyvinyl]pyridine-2-yl}acetamide; 2-({5-[2-hydroxypyridine·3-ylethylene) Base]_7_methoxyl,3_dihydroimidazolium [l,2-c]oxazoline-8-yl}oxy)_ 沁 dimethyl acetamide; 2-[7-methoxy Tetrahydropyran-2-ylmethoxy)-2,3-dihydrooxazole 5-[1,2-c]oxazolin-5-yl]-1-pyridin-3-ylvinyl alcohol; 2-0 (2-hydroxyethoxymethoxy-2,3-dihydroimidazo[nqoxazol-5-yl]-1-pyridylvinyl alcohol; (5-[2-hydroxy-2- Pyridylvinyl]-7-methoxy-2,3-dihydroimidazo[l,2-c]oxazoline-8-yl}oxy)acetic acid; 10 4_({5_[2-hydroxy_ 2" 〇 乙烯基 vinyl [7_decyloxy-2,3-dihydroimidazo[l,2-c]oxazol-8-yl}oxy)butyric acid; ({5-[2_ Hydroxy-2-pyridin-3-ylvinyl]-7-decyloxy-2,3-dihydroimidazo[l,2-c]oxazoline-8-yl}oxy)acetonitrile; 2-0 Methoxy-8-(2H-tetrazol-5-ylmethoxy)-2,3-diimidazolium 15 [丨,2-0]oxazoline-5-yl]-1-pyridine-3 -vinyl alcohol; 2-[7-decyloxy-8-(4-orfosin-4-yl-4-ketobutoxy) _2,3·»-ismidazo[l,2-c]oxazolium-5-yl]-1-pyridin-3-ylvinyl alcohol; 5- [1-hydroxy-2-(8-morpholine) 4-yl-2,3-diimidazo[i,2_c]oxazolium-5-yl)vinyl]pyridin-3-ol; 20 N-(2,3-dihydroimidazo[1, 2-c]oxazoline-5-yl)-5-hydroxynicotinium amide; 6-(acetamido)-N-(7,9-dimethoxy-8-methyl-2,3 - Dihydrogen taste. Sit and [l,2-c]oxazolium-5-yl)nicotinamide; N-(8,9-dimethoxy-2,3-dihydroimidazo[1, 2-c]carbazole-5, meaning)$ -24- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)

200413379 V. Invention Description Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed on the basis of acid test amine; 5--based-N-(7-methoxy-2,3, in the test of decylamine; N (7,8- Monomethoxy-2,3-dihydroflavor [(4-methoxybenzyl)oxy] in the base amide; N (7,8--decyloxy-2,3-dihydroimidazolium ^ ,2-c]carbazole _5_yl)_^ Μ based on the amine; 5 L-yl-[-(difluoromethyl) 2,3-dihydroimidazo[He]carbazole Amino acid; N-{H3_(1,3-diketo),3.dihydro.-isoindole 2_yl)propoxy]· 2,3-dihydroimidazo[ He]carbazol-5-yl-nicotinium amide; N-(7H-decyloxy-2,3-dihydroimidazo[10) kun quinozoic _5-yl) nicotine guanamine; '6- Amino-N-(8-decyloxy-2,3-dihydro-flavor. Sit and n, 2-c;] l^t5-&) 15 in the amine; benzimidazole-5-yl) _2-(8,9-Dimethoxy-2,3-dihydroimidazo[l,2-c]indazol-5-yl)vinyl alcohol; 2-(8,9-monomethoxy_ 2,3-dihydromethane. Sit and [1,2<]11 Kui 12 Lin-5-yl)-1-(2,4-dimercapto-l,3-thiazol-5-yl)- Vinyl alcohol; N-(9-decyloxy-2,3-dihydroimidazo[i,2-c]oxazoline)-丨^^benzimidazole-5- Indoleamine; N-(8-bromo-2,3-dihydroimidazo[i,2-c]oxazolin-5-yl)nicotinium amide; N-(8-bromo-2,3-di Hydrogen sniffing [i,2-c]carbazole u-Lin-5-yl)-iH-benzopyrene-5-decylamine; hydrogen ytterbium sitting [1,2-c]n|. _5_基) Pack 10 20 -25- This paper scale applies to China National Standard (CNS) A4 specification (210x297 public). Order line 200413379 A7 V. Invention description (24 N-(8-甲格2,3_ Dihydro „ 唾 并 ( (10) 今 蛛 亚 亚 亚 亚 ; ^ ^ ^ ^ ^ ^ ^ ^ ^ ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 5-nonylamine; 5 Ν^ΓΓ^methyl>2,3_dihydromilybdenum. Kui's final 5·yl HH-this is a taste of salivary-5-bristamine; (fluorine, 3-monoimidazo[ With small quizazo-5-pyridin-5-nonylamine; Ν-(7-methoxy-2,3_dihydro-salt and sputum j-base) in the test of 10 amines; N-(8 greedy 2,3_ dihydrogen taste. Sit and [to Xiaokui 咐 _5_ base hh- stupid and mouth rice 嗤-5-decylamine; 6-(acetamido)-N pufufen ice base _ 2,3_Dichloro-flavored and is alkaloid in the form of a quinone-based group; 15 Η1Η·benzimidazolyl)-2-(8-morphine-4-yl-2,3 -dihydroimidazole and [l,2-c]4oxazol-5-yl)B Alcohol;,, Ν-{5-[1-hydroxy-2-(8-?-fusin-4-yl-2,3-dihydroimidazo[^^唼·Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative Zoxadino-5-yl)vinyl]pyridine_2-yl}acetamide; 6-methyl-N-(8-morpholin-4-yl-2,3-dihydroimidazo[1,2 -c]carbazole _ 20 5-yl) nicotinamide; 1-(1H-stupid. Sodium-5-yl)-2_[8-(4-methylhexahydrogen 0 to ° small base)-2 dihydroimidazo[l,2-c]oxazolium-5-yl]vinyl alcohol; (2,3-dihydro-flavored wand [1,2<]. Kui sal 17 Lin-5-yl)-311-mouth rice. Sit and [45 seven] pyridine-6-decylamine; -26- This paper scale applies to China National Standard (CNS) A4 specifications (21〇x297 public Chu) 200413379 A7

10 N-(7,8-Dimethoxy-2,3-dihydroweiswa and 3H-imidazo[4,5-b]acridin-6-decylamine; 叩-^曱yl(4)-dihydrogen (d) and similar to the outer quinone saliva-based (four) benzimidazole-5-decylamine; N-(7,9-dimethoxy-2,3-dihydro taste σ sitting and like the outer quinine to the b 5 base) _ 1Η-stupid and taste wow-5-acid amine; 1{5-[2-(7,9-monomethoxy-8-methyl-2,3-dihydro-, sit and [1,24] Said oxazol-5-yl)-1-hydroxyvinyl]pyrridine_2-yl}ethyl"咁-5-yl)-1-hydroxyvinyl]pyridine_2-yl}acetamide; 2-(8,9-Dimethoxy-8-mercapto-2,3-dihydroimidazo[nqcarbazole]-1-° ratio -3--3-ethyl alcohol; mutual mutual benefit Structure or stereoisomer form, pharmaceutically acceptable 5-salt 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 In addition, the present invention provides an agent comprising one of the above compounds and optionally selected A pharmaceutically acceptable excipient. The alkyl group itself and in the alkyl group, the alkoxy group, the alkyl fluorenyl group, the alkylamino group, the alkylamino group, the acryl group, the alkyl group, the alkyl ester group, the alkyl ester group and the alkyl ester group "alk" and, alkyl, in the alkylalkylamino group, represent a straight or branched chain group, usually containing from 1 to 6, more preferably from 1 to 4 and particularly preferably from 1 to 3 carbon atoms, representative Preferably, it is preferably methyl 'ethyl, propyl, isopropyl, isobutyl, tert-butyl, t-butyl, pentyl, n-hexyl, and the like. The exothermic group represents a divalent straight or branched chain saturated hydrocarbon group containing only carbon and hydrogen. -27- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm). 200413379 A7 B7 V. Description of invention (26) Atom , usually containing 1 to 6 carbons, more preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms, representatively illustrated and more preferably an anthracene group, an extended ethyl group, a 2-methyl extended propyl group, a butyl group Base, 2-ethylbutylene, and the like. Alkoxy is representative and preferably methoxy, ethoxy, n-propoxy 5, isopropoxy, tert-butoxy, n-pentyloxy, n-hexyloxyalkylamine represents one or Alkylamino groups of two (independently selected) alkyl substituents, illustrative and preferably represent methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamine , N,N-di-10-methylamino, N,N-diethylamino, N-ethyl-N-decylamine, N-methyl-N-n-propylamino, N-isopropyl-N - n-propylamino group, N. tert-butylmethylamino group, N-ethyl-N-n-pentylamino group, N-n-hexylmethylamino group and the like. The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed alkylaminocarbonyl represents a group containing one or two (independently selected) alkyl substituents, indicating and preferably represents amidinocarbonyl, ethylaminocarbonyl, 15 Alanylcarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-B Aminocarbonyl, N-fluorenyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl- N-n-pentylaminocarbonyl, N-n-hexylmethylamine 20-based carbonyl, and the like. The alkylaminosulfonyl group represents an alkylaminosulfonyl group containing one or two (independently selected) alkyl substituents, and preferably represents a methylaminosulfonyl group, an ethylaminosulfonyl group, N-propylaminosulfonyl, isopropylaminosulfonyl, second butylamine yellow S basket, n-decylamine acid base, n-hexylamine yellow -28- This paper scale applies to China National Standard (CNS) A4 Specification (210x297 mm) 200413379 Α7 Β7 V. Description of invention (27) Acid group, N,N-dimethylamine group S blue group, hydrazine, hydrazine-diethylamine group · broth, N-ethyl- Ν-methylamine sulphate, Ν-fluorenyl Ν-n-propyl propyl sulphate, Ν _ isopropyl-hydrazine-n-propylaminosulfonyl, hydrazine, tert-butyl-hydrazine-methylamine sulfonate Anthracenyl, fluorenyl-ethyl-hydrazine-n-pentylaminosulfonyl, fluorenyl-n-hexyl-fluorene-nonylaminosulfonyl 5 fluorenyl and the like. Alkylsulfonyl indicates and preferably represents methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, n-hexylsulfonate醯基等. The alkyl ester group is illustrative and preferably represents a methyl ester group, an ethyl ester group, a n-propyl ester 10 group, an isopropyl ester group, a tert-butyl ester group, a n-pentyl ester group, a n-hexyl ester group and the like. The alkyl ester group amines are illustrative and preferably represent a methyl ester group amine group, an ethyl ester group amine group, a n-propyl ester group amine group, an isopropyl ester group amine group, a tert-butyl ester group amine group, a n-pentyl ester group amine group. , n-hexylamino group and the like. The alkanoylamino group is illustrative and preferably represents an acetamino group, an ethylcarbonylamine 15 group or the like. The cycloalkyl group itself and the cycloalkylamino group and the cycloalkylcarbonyl group represent a cycloalkyl group usually having 3 to 8 and preferably 5 to 7 carbon atoms, and preferably represent a cyclopropyl group, a cyclobutyl group, and a ring. Pentyl, cyclohexyl, cycloheptyl and the like. The Intellectual Property Department of the Ministry of Economic Affairs, the Intellectual Property Office, and the Consumer Cooperatives, which prints the aryl group and the "aryl group" of 20 in the arylamine, arylcarbonyl, alkoxyaryl group, represent a single to three of usually 6 to 14 carbon atoms. The cycloaromatic carbocyclic group is illustrative and preferably represents a phenyl group, a naphthyl group, a phenanthryl group or the like. The arylamino group represents an arylamine group having one or two (independently selected) aryl substituents, and preferably represents a phenylamine group, a diphenylamino group, a naphthylamino group or the like. -29- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed clothing five, invention description (2 〇 芳 芳 basic and in the heteroaryl "Heteroaryl" in the amino and heteroarylcarbonyl group represents a aryl group generally having 5 to 15 and preferably 5 or 6 ring atoms and up to 5 and preferably up to 4 hetero atoms selected from the group consisting of S, fluorene and N. a family of mono- or bicyclic groups, indicating and preferably representing a thiol group, a furyl group, a pyrrolyl group, a fluorenyl group, a sigma group, a miso base, a 嗟σ siting group, a 咐σ well group, a σ ratio Base, σ-dense base, tower σ well base, porphinyl, fluorenyl, isodecyl, 吲σ, benzofuranyl, benzothienyl, fluorenyl, isoindolyl, 1 , 3-benzodioxanyl, benzofuranyl, benzofuran-2,5-diyl, benzofuran-3,5-diyl, etc. 10 The heterocyclic ring itself and the heterocyclic ring itself usually contain 4 To a 10 and more preferably 5 to 8 ring atoms and up to 3 and more preferably up to 2 mono- or polycyclic groups selected from hetero atoms and/or hetero groups including fluorene, 0, S, SO and S02, heterocyclic groups Can be saturated or part Unsaturated, preferably a 5- to 8-membered monocyclic saturated heterocyclic group containing up to 2 heteroatoms selected from the group consisting of hydrazine, N and S, and more preferably tetrahydrofuran-2-yl, pyrrolidine -2-yl, pyrrolidin-3-yl, pyridinyl, hexahydropyridinyl, morpholinyl, perhydroazepine. Heterocyclylcarbonyl indicates and preferably represents tetrahydrofuran-2-ylcarbonyl , pyroline-2-yl, 咐13 唆-3-yl-yl, fluorenyl-Wiki, hexa- 20-hydropyridylcarbonyl, morphinylcarbonyl, perhydroheptylcarbonyl. Halogen And the halo group represents fluorine, chlorine, bromine and/or moth. Further, the present invention provides an agent comprising one of the above compounds and optionally a pharmaceutically acceptable excipient. The scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm)

200413379 A7 B7 V. INSTRUCTION DESCRIPTION (29) The compound of the formula (I) of the present invention can be prepared, but not limited to, by the following reaction, and in some embodiments, one or more of the compounds used as starting materials or intermediates Substituents such as amine, thiol and thiol are preferably protected by protecting groups well known to those skilled in the art, and Example 5 of protecting groups is disclosed in Greene & Wuts' 'Protective Groups in Organic Synthesis (3nd Edition)' '. The compound of the formula (1) of the present invention can be produced, but not limited to, by the following method [A] or [B]. Compound of formula (I-a):

(wherein R1, R5, R6, Y1, Y2, Y3, Z1, Z2, Z3 and Z4 are the same as defined above) can be, but is not limited to, prepared by the following Method A.

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. INSTRUCTION DESCRIPTION (3〇) The compound of formula (Ia) can be, for example, via a compound of formula (where Y1, Y2, Y3, z1, z2) , Z3 and Z4 are the same as defined above and are prepared by reacting a compound of formula (III) wherein R1, R5 and R6 are the same as defined above and represent a CK6 alkyl group. 5 The reaction can be carried out in the absence of a solvent or in a solvent, including, for example, ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran (butyl HF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as stupid , benzene and xylene; guanamines such as N,N-dimethyl decylamine (DMF), N,N-dimethylacetamide and N_mercaptopyrrolone; sulfoxides such as diterpenoids Sulfone (DMS); alcohols such as methyl alcohol, ethanol, 1-propanol, isopropanol and tert-butanol; water and ethers, two or more solvents selected from the above list may be mixed and used as needed. The reaction temperature can be set as needed depending on the compound to be reacted, and the reaction temperature is usually, but not limited to, about 10. 〇 to 2 〇 (rc, and preferably about 5 〇. 〇 to 16 〇 c, the reaction can be carried out usually for 10 minutes to 48 hours and more preferably 3 〇 minutes 15 to 24 hours. Preparation of intermediates (ΙΓ Compounds (wherein Υ1, Z1, Z2, Z3, and Z4 are the same as those defined by the Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperation, social printing system, γ2 and Υ3 independently represent cmNR4 and are connected via a single bond) and ') Compound (wherein γ ΐ 1 1 2 2 z3 and z4 are 20 identical to the above definition, γ 2 and Y 3 independently represent CH or N and Γ is linked by a double bond) may be, but is not limited to, prepared by the following method. ] This paper ruler money and money ^ Zhun-32- 200413379 A7 B7 V. Invention description (31

VI XN Step 1 NH0 ¥

NH. η γ- 士士 rz;

\\ 3 / 丫nh2 装 Installed in step 1, compound of formula (ΙΓ) (where Υ1, Ζ1, Ζ2, Ζ3, and ζ4 are the same as defined above, Υ2 and Υ3 independently represent CR3R4 or NR4 and are connected via a single bond) It can be prepared, for example, by reacting a compound of the formula (VI) wherein Z1, Z2, Z3 and Z4 are the same as defined above with a diaminoalkane derivative such as ethylenediamine. The reaction is suitably carried out using an appropriate dehydrating agent such as S〇C12, P0C13, P2O5, P2S5, cs2 and others. This reaction can be carried out in the absence of a solvent or in a solvent, and includes, for example, ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethylhexyloxyethane; aromatic hydrocarbons such as benzene. , benzene and xylene and others, two or more solvents selected from the above list may be mixed and used as needed. The printing reaction temperature of the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative is usually, but not limited to, about 10 ° C to 200 ° C, and preferably about 50 ° C to 200 ° C, and the reaction can be carried out usually for 10 minutes to 48 hours. It should be 30 minutes to 24 hours. 20 In step 2, a compound of the formula (wherein Υ1, Ζ1, Ζ2, Z3 and Z4 are the same as defined above, and Y2 and Y3 independently represent CH or N and are linked via a double bond) may be via the use of a reagent such as Tn02, ΚΜη04 and other compounds from the formula (ΙΓ) via oxidation reaction or using Pd/C via dehydrogenation reaction (where Y1, Z1, Z2, Z3 and Z4 are the same as defined above, -33- This paper scale applies to Chinese national standards ( CNS) A4 Specification (210x297 mm) 200413379 A7 B7 V. INSTRUCTION DESCRIPTION (32) Y2 and Y3 independently represent CR3R4 or NR4 and are prepared via a single bond connection). This reaction can be carried out in a solvent, and includes, for example, scales such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethoxyethane; aromatic hydrocarbons such as benzene, toluene and Toluene; dimethyl decylamine (DMF), dimethyl acetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(111)-pyrimidinone (DMPU) , 1,3-dimethyl-2-imidazolidinone (DMI), N-decylpyrrolidone (NMP) and others, two or more solvents selected from the above list may be mixed and used as needed. The reaction temperature is usually, but not limited to, about 〇 ° C to 200 ° C, and preferably about 50 ° C to 200 ° C, and the reaction can be carried out usually for 10 minutes to 48 hours and preferably for 30 minutes to 24 hours. Compounds of formula (VI) can be obtained from commercial sources or synthesized via conventional methods. The compound of the formula (III) can be produced, for example, by the following method [A-ii]. Method [A-ii]

The Ministry of Economic Affairs Intellectual Property Office staff consumption cooperative prints a compound of formula (III) (wherein L, R1, R5 and R6 are the same as defined above) via a compound of formula (VII) (wherein R1, R5 and R6 are the same as -34) - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 5. Inventive Note (33) The above definition) and the compound of formula (VIII) (where L is the same as defined above) It is prepared by, for example, potassium hydride, hexamethylene sulphate, and other reactions in the presence. This reaction can be carried out in a solvent including, for example, an ether pigment such as diethyl ether, 5 isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; an aromatic hydrocarbon such as benzene, toluene and Toluene; dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1Η)-σ dimethyl ketone (DMPU), 1,3-dimethyl-2-anthranone (DMI), Ν-methylpyrrolidone (ΝΜΡ) and others, two or more solvents selected from the above list can be mixed as needed use. The reaction temperature is usually, but not limited to, about -100 ° C to 100 ° C, and the reaction can be carried out usually for 30 minutes to 48 hours and more preferably 2 hours to 12 hours. Alternatively, the compound of the formula (III) can be produced, for example, by the following method [A-iii]. Method [A-iii]

R5\ R6 1 R\.R6 RVL' + HOrV°*L ^RW°'L 〇〇〇〇0 20 IX X III Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed (III) compound (where L, R1 , R5 and R6 are the same as defined above) and can be passed through the compound of formula (IX) (wherein R1 is the same as defined above -35- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 5. Description of the invention (34) and L' is a release group such as a halogen atom such as a chlorine or bromine atom or an imidazole, and a compound of the formula (X) wherein L, R5 and R0 are the same as defined above or a salt thereof, for example Prepared by reacting potassium salt. The reaction can be carried out in the presence of a Lewis acid including a magnesium salt such as magnesium bromide, magnesium chloride, magnesium iodide, magnesium acetate, and other or a base such as n-butyllithium, dibutyllithium, and the like. It is carried out in a solvent, and includes, for example, ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene, and others, Or a plurality of solvents selected from the above list may be mixed and used as needed. Preparation of the compound of formula (I-b):

(wherein R1, Y1, Y2, Y3, Z1, Z2, Z3 and Z4 are the same as defined above) can be, but is not limited to, prepared by the following Process B. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing method [B]

-36- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Inventive Note (35 Compounds of formula (Ib) can be via compounds of formula (IV) (where Y1, Y2, Y3, Z1 , Z2, Z3 and Z4 are the same as defined above) and a compound of formula (V) wherein R1 is the same as defined above and L is a cleavage group such as hydroxy

T 〇 < /R1 5 group; halogen atom such as chlorine, bromine or iodine atom; imidazole or • I 4 count it ·! where R1 is the same as defined above), in the case where L" is a hydroxyl group, The reaction is suitably via the use of a coupling agent such as benzotriazol-1-yloxy-pyrrolidinyl squamous hexafluorophosphate (PyBOP), 1,1'-carbonyldi(1,3-imidazole) (CDI), 1, 1'-carbonylbis(1,2,4-triazole) (CDT) and other 10 are carried out. /〇YR1 In the case where L" is a halogen atom, imidazole or "", the reaction is suitably carried out in the presence of the test. Including, for example, σ 唆, triethylamine and hydrazine, hydrazine-diisopropylethylamine, dimethylaniline, diethylaniline, and 15 thereof. This reaction can be carried out in the absence of solvent or in a solvent, including, for example, ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxy. Ethane; aromatic hydrocarbons such as benzene, toluene and dinonylbenzene; nitriles such as ethyl acetate f; guanamines such as hydrazine, hydrazine-dimethyl decylamine (DMF), hydrazine, hydrazine-dimercapto 20 Indoleamine (DMAC) and Ν-methylpyrrolidone (ΝΜΡ); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); sub-difficults such as diterpenoid (DMS) and others Two or more solvents selected from the above list may be mixed and used as needed. The reaction temperature is usually, but not limited to, about 40 ° C to 200 ° C and is preferably about 20 - 37 - This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 x 297 mm). 200413379 A7 B7 V. Description of Invention (36) From C to 180 ° C, the reaction can be carried out usually for from 30 minutes to 48 hours and more preferably from 2 hours to 12 hours. Preparation of Intermediates The compound of the formula (IV) can be, but is not limited to, prepared by the following method [B-i] 5 Preparation Method [B-i]

• I 4 metering •! ^1-ύ!

f '丁 N 10

Compounds of formula (IV) wherein Υ1, Υ2, Υ3, Ζ1, Ζ2, Ζ3 and ζ4 are the same as defined above may be via compounds of formula (II) (wherein Υ1, Υ2, Υ3, ζ1, ζ2, ζ3 and ζ4) It is the same as defined above) and is prepared by reacting cyanide halide 15 with cyanogen bromide. This reaction can be carried out in the absence of solvent or in a solvent, including, for example, ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxy. Ethane; aromatic hydrocarbons such as benzene, toluene and dinonylbenzene; guanamines such as N,N-dimercaptomethylamine (DMF), N,N-dimethylacetamide and N-mercapto 20 Pyrrolidone; alcohols such as decyl alcohol, ethanol, 1-propanol, isopropanol and tert-butanol, and others, two or more solvents selected from the above list may be mixed and used as needed. The reaction temperature is usually, but not limited to, about -10 ° C to 200 ° C, and the reaction can be carried out usually for 30 minutes to 48 hours and more preferably 1 hour to 24 hours. -38- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Inventive Note (37) Compound of formula (II) (where Y1, Y2, Y3, z1, Z2, Z3 and Z4 It is the same as defined above) can be prepared by the same method as disclosed in the method [A-Ι]. Compounds of formula (VII), (VIII), (IX) and (X) can be obtained from commercial supply 5 or synthesized by conventional methods. When the compound of the formula (I) or a salt thereof has an asymmetric carbon in the structure, an optically active compound and a racemic mixture are also included in the scope of the present invention. Typical salts of the compounds of the formula (I) include salts prepared by reacting the compound 10 of the present invention with an inorganic or organic acid or an organic or inorganic base compound, and these salts are referred to as acid addition and base addition salts, respectively. . The acid forming the acid addition salt includes inorganic acids such as, but not limited to, sulfuric acid, phosphoric acid, hydrogen acid, hydrobromic acid, hydroiodic acid, etc., and organic acids such as, but not limited to, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromo Phenylsulfonic acid, carbonic acid, amber 15 acid, citric acid, benzoic acid, acetic acid, and the like. Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperation 钍 printing alkali addition salts include derived from inorganic bases such as, but not limited to, ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, carbonates, hydrogencarbonates, etc. and organic bases For example, but not limited to, salts such as ethanolamine, triethylamine, tris(hydroxyindenyl)aminomethanone, and inorganic examples include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, carbonic acid. Potassium hydrogen, calcium hydroxide, calcium discate, and the like. The compound of the present invention or a salt thereof, depending on its substituent, may be modified to form a lower alkyl ester or other known ester; and/or a hydrate or other solvate, these esters, hydrates and solvents. The compounds are included in this -39- __ — ----------------- - - _ . _________ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 _ B7 V. Description of invention (38) Within the scope of the invention. The compound of the present invention can be administered orally, for example, but not limited to, a fat-coated tablet, a capsule, a pill, a powder, a granule, a granule, an elixir, a solution, a suspension, a syrup, a solid and a liquid aerosol. And the emulsion, 5 which may also be used in the form of a non-fat, such as, but not limited to, intravenous, intraperitoneal, subcutaneous, intramuscular, etc., which are generally known to those skilled in the art, and the compounds of the present invention may be intranasally The form is administered via topical use of a suitable intranasal device, or via a skin route using a transdermal delivery system generally known to those skilled in the art. 10 In general, when the skilled artisan uses the compounds of the present invention, a number of factors of the selected method of administration include, but are not limited to, the age, weight, sex, and health of the subject, the severity of the condition being treated, The route of administration, the degree of metabolism and excretion of the subject, the form of administration used, the particular compound used and its salts. 15 The compounds of the present invention are formulated with excipients that are preferably printed with one or more pharmaceutically acceptable Ministry of Commerce, Intellectual Property Office employees, consumer cooperatives, excipients are inert materials such as, but not limited to, carriers, diluents , flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, adhesives, tablet decomposers and sealants. Another embodiment of the invention is a pharmaceutical preparation comprising a compound of the formula 20 which is compatible with the other ingredients of the preparation and which does not harm the subject to be treated - or a plurality of pharmaceutically acceptable The preparation of the preparation of the present invention is carried out by mixing an effective amount of a compound of the present invention and one or more pharmaceutically acceptable excipients, in the preparation of the composition of the present invention: the active ingredient may be mixed with a diluent , or contained in the carrier, in the form of a carrier -40-^________ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297^^-- -- 200413379 A7 B7 5. Invention Description (39) Can be a capsule , capsule, paper or other container, the carrier may be used as a diluent, which may be a solid, semi-solid or liquid material as a vehicle, or may be a tablet, a pill, a powder, a lozenge, an elixir, a suspension, an emulsion , solutions, multidrugs, aerosols, ointments containing, for example, up to 10% by weight of active compound, 5 and soft and hard gelatin capsules, suppositories, sterile injectable solutions, and aseptically packaged powders. The ingredients may be combined with an oral and non-toxic pharmaceutically acceptable carrier such as, but not limited to, lactose, starch, sucrose, dextrose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium retinate, methyl Cellulose, etc.; and if necessary, decomposing agents such as, but not limited to, corn starch, methyl cellulose, agar, bentonite, xanthan gum, succinic acid, etc.; and optional adhesives such as, but not limited to, gelatin, natural sugars , point-lactose, corn sweetener, natural and synthetic gum, gum arabic, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, soil, etc.; and 15 depending on the desired lubricant, for example However, it is not limited to magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium alginate, sodium acetate, sodium chloride, talc, etc. The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative is printed in the form of powder. The carrier is a finely divided solid and is mixed with the active ingredient of the micro-divided granules, and the active ingredient is mixed with a carrier having adhesive properties at a suitable ratio and extruded into a shape and a large shape required for tablet production. Preferably, the powders and tablets preferably contain from about 1 to about 99% by weight of the active ingredient of the novel compositions of the invention. Suitable solid carriers are 竣methylcellulose low melting waxes and cocoa butter. 'Aseptic liquids Modulations including suspensions, emulsions, slurries and brewing active ingredients may be dissolved or suspended in a pharmaceutically acceptable carrier, eg sterile-41- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 public interest) 200413379

, invention description 5 10 15 Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Co., Ltd. Printed 20 water, halogen-free organic solvents, or a mixture of sterile water and sterile organic solvents. The product can also be dissolved in a suitable organic solvent such as an aqueous solution, which can be produced by dispersing the active ingredient of the micro-divided particles in aqueous powder or carboxymethyl...', sodium solution or a suitable oil. Other compositions. The product is in the form of a single (10) drug, which contains a unit dose of 4 separate doses to other human mammals, unit dosage form, one capsule or tablet, or multiple capsules or tablets. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Change or light between. The scope of the pen gram from the appearance (4) is mg / kg / day = kg days to about 100 mg / kg / day, preferably from 0.1 = / day to 30 mg / kg / day, and most suitable from V / day to About 10 vouchers / haired brothers - 浐 浐 沾 : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : ^ Day, the object can be used daily for 1 day to 1 gram / kg / day, the compound of the invention for two or three days, or the total daily dose is divided into several doses, each continuous medication. Once in a while, when the delivery is through the form of a skin, it is of course the following example form, but it cannot be limited by the spirit or scope of any cost. In the J Ling case, if not stated otherwise, all quantitative data 42-

Binding line 200413379 A7 B7 V. Invention description (41) is about weight percentage. 4 NMR spectra were recorded using a Bruker DRX-300 (300 MHz for 4) spectrometer or a Bruker 500 UltraShieledTM (500 MHz for 1 Η) with a chemical shift of 0 ppm using tetramethyl decane (TMS) as the internal 5 mark. Millions of components (ppm) reported that the coupling constant (J) is expressed in Hertz and the abbreviations s, d, t, q, m, and br are unimodal, double-split, tri-split, tetra-crack, and Split peaks and broad peaks were determined using MAT95 (Finnigan MAT). The liquid chromatography-mass spectrometry (LC-MS) data printed by the Intellectual Property Office of the Ministry of Economic Affairs is used in a Micromass Platform LC equipped with a Shimadzu 10 Phenomenex ODS column (4.6 mm 0 X 30 mm) with acetonitrile-water (9: 1 to 1:9) Flow-through recording at a flow rate of 1 ml/min, mass spectrometry using electron atomization (ES) free technique (Micromass Platform LC), and pre-coating of a silicone-coated plate (Merck® 60F-254) TLC, 矽15 gel (WAKO-Glue C-200 (75-150 μm)) was used for all column chromatography. All chemicals were reagent grade and purchased from Sigma-Aldrich, Wako pure chemical industries, Ltd. , Tokyo kasei kogyo Co., Ltd., Nacalai tesque, Inc., Watanabe Chemical Ind. Ltd., Maybridge plc, Lancaster Synthesis Ltd., Merck KgaA, Kanto Chemical 20 Co., Ltd. The effects of the compounds of the invention were tested by the following test methods. [Measurement of IC50 value of compound in 激酶3Κτ kinase test] Chemicals and test materials Phosphoinositide (Ptdlns) and phospho-silic acid (PtdSer) are purchased from -43- This paper scale applies to China National Standard (CNS) A4 Specifications (210x297 mm) 200413379 A7 B7 V. Description of invention (42)

DOOSAN SERDARY RESEARCH LABORATORIES (Toronto, Canada), recombined human PI3K r (His6-tag full length human PI3K pi 10 7 fused at the C-terminus in S. frugiperda 9 insect cells) was obtained from ALEXIS BIOCHEMICALS ( #20卜5 055-C010; San Diego, CA), [r 33P]ATP and unlabeled ATP were purchased from AMERSHAM PHARMACIA BIOTECH (Buckinghamshire, UK) and ROCHE DIAGNOSTICS (Mannheim, Germany), scintillation blend and MicroScint PSTM is available from PACKARD (Meriden, CT) and MaxisorpTM is available from 10 NALGE NUNC INTERNATIONAL KK (Toyoko,

Japan), all other chemicals not further specified were obtained from WAKO PURE CHEMICALS (Osaka, Japan). Solid-Phase Liposome Kinase Assay To evaluate the inhibitory effect of compounds on PI3K7, 15 MaxisorpTM plates were coated with 50 μg/ml ptdIns& 5 μg/ml PtdSer dissolved in 50 μm of gas-like:ethanol (3:7) Rise/tank solution, then air dry the plate by incubating in a fume hood for at least 2 hours, via mixing 25 μl/well test buffer 2x (1 〇〇 millimolar concentration Ministry of Economics Intellectual Property Bureau employee consumption cooperative print M 〇PSO/NaOH, 0.2 molar concentration NaCl, pH 7.0, 8 millimolar concentration 2 M MgCl2, 2 house gram / 3⁄4 liter BSA (no fatty acid)) and 5 〇 ng /

The well PI3K γ was plated with a liposome pre-coated and 10 χ test compound in 2% DMSO was added to establish the reaction via the addition of 2 〇 microliter/tank ATP mixture (final 10 micromolar concentration Ατρ; 〇〇5/ The tank [^ 33P]ATP) starts the reaction, and after incubation for 2 hours at room temperature, the Chinese National Standard (CNS) A4 specification (210x297 public) is applied by adding 5〇-44- this paper scale. 200413379 A7 V. Description of invention ( 43 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Microliter/Slot Stop Solution (50 mM EDT, pH 80) The reaction was terminated and the plate was washed with Tris-buffered saline (TBS, pH 7 4). Twice, add Micr〇Scint pSTM (PACKARD) flashing mixture at 100 μl/well, and count the radioactivity using a T〇pC〇untTM (PACKARD) flash counter. Calculate the percent inhibition of each concentration of the compound and take the inhibition curve Determination of IC50 value [Isozyme selectivity test in PI3K] {Measure ic5 化合物 value of compound in PI3K /3 kinase test method} 13 feet / 3 卩 110 points and 031 ^ 85 〇; Virus is obtained from Dr. Katada (University of Tokyo), according to manufacturing Description (pharmingen, San Diego, CA) Co-recombinant PI3K hetero complexes of pi 10 /3 and GST-P85 α are co-expressed in insect cells and purified using a glutamic acid affinity column, similar to the kinase in ΡΙ3Κτ The IC50 value of the compound is determined in the test method. Partially disclosed method is prepared for the kinase assay of Κ3Κ/3. [Selection Test of Other Kinases] The kinase selectivity of the compounds was evaluated using several kinase assays such as the kinase assay of Syk. {Syk Road Amino Acid Kinase Inhibition Test Method for Selective Enzymes} 20 (1) Preparation of Syk protein by RT-PCR method from human Burkitt's lymphoid b cell line Raji (American Type Culture 〇11) Total RNA replication encodes cDNA fragments of the human Syk open reading architecture, inserts cDNA fragments into pAcG2T (Pharmingen, San Diego, CA) to establish baculovirus transfer 10 15 -45- This paper scale applies to Chinese National Standard (CNS) A4 specifications (210x297 mm)

200413379 A7 __________ B7 V. INSTRUCTIONS (44) Carrying the bacteria, then using the bacteria and linear baculovirus (BaculoGoldTM, Phannungen) for transfection of sm cells (Invitr〇genDieg〇, CA) Baculovirus and expansion of MSf21 cells, so that Sf2i cells were transfected with this expanded high-valent virus to produce a transfer protein of Syk kinase fused with glutamine-sulfur-transferase (GST). The resulting GST-Syk was purified using a glutamine sulfur column (Amersham Pharmacia Biotech AB, Uppsala, Sweden) according to the manufacturer's instructions, and the purity of the protein was confirmed to be higher than 90% by SDS-PAGE. 10 (2) Synthesis of peptides Next, peptide fragments containing 30 residues of two tyrosine residues KISDFGLSKALRADENYYKAQTHGKWPVKW were synthesized via a peptide synthesizer, and then the N-terminus of the fragments was biotinylated to obtain a biotinylated activation ring. Peptide (AL). 15 (3) Measurement of Syk retinoic acid kinase activity The Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperation, all the reagents printed by the company are Syk kinase test buffer (50 millimolar concentration Tds-HCl (pH 8.0), 10 millimeters Mole concentration MgCl2, 0.1 millimolar concentration Na3V04, 〇.l〇/〇BSA, 1 millimolar concentration DTT) diluted, first, a mixture containing 3.2 micrograms of GST-Syk and 0.5 micrograms of AL (35 20 microliters) Place into each well of a 96-well plate, then add 5 μl of test compound in the presence of 2.5% diterpene (DMS0) to each well, and add 300 μmol ATP (10 μl) to the mixture. The kinase reaction was initiated, and the final reaction mixture (50 μl) contained 0.65 nanomolar concentration of GST-Syk, 3 micromolar concentration AL, 30 micromolar concentration ATP, and -46- paper scale applicable to Chinese national standards. (CNS) A4 specification (210 X 297 mm) 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Inventive Note (45) Test compound, 〇.25% DMSO and Syk kinase test buffer. The mixture was incubated for 1 hour at room temperature (RT) via the addition of 120 microliters of stop buffer (50 millimolar Tris-HCl (pH 8.0), 10 millimolar EDTA, 500 millimolar NaCl, 0.1%) BSA) The reverse 5 should be terminated, the mixture was transferred to a Streptomyces-coated plate and cultured for 30 minutes at room temperature to bind biotin-AL to the plate with Tris-buffered saline containing 0.05% Tween-20 (TBS) (50 millimolar concentration Tris-HCl (pH 8.0), 138 millimolar NaCl, 2.7 millimolar KC1) After the plate was washed 3 times, it was previously labeled with 铕 by Amersham Pharnacia's kit 10 Containing 50 millimolar Tris-HCl (pH 8.0), 138 millimolar NaCl, 2.7 millimolar KC1, 1% BSA, 60 ng/3⁄4 liter of monoclonal antibody against linoleic acid, 100 μl of antibody solution from 4G10 (Upstate Biotechnology) and incubated for 6 min at room temperature, after washing, add 100 μl of fortification solution (Amersham 15 Pharnacia Biotech) and then pass through multiple at 400 microsecond delay and 400 microsecond window The indicator juice ARVO (Wallac, 〇y, Finland) is used for excitation at 340 nm and for 615 nm for radiation. Measurement time - dissociated fluorescence. [Measurement of IC50 value of compound in superoxide production from human peripheral monocytes] Extraction from healthy human volunteers via venipuncture with a 50 ml injection needle containing 50 units of heparin (1 〇〇 升 / supply Red blood cells were removed by incubation with 1% (w/v) dextran and 45% (w/v) glucose for 30 minutes at room temperature. After centrifugation at 350 xg for 10 minutes, the platelets were resuspended in milli-47- 7's scale applies to China National Standard (CNS) A4 specification (210 X 297 public) ' ' "— --

200413379 A7 B7 V. INSTRUCTIONS (46) liter PBS, gently stratify the cell suspension in a gradient of 50 ml test tube in PBS (#2335-050, Iwaki, Japan) 20 ml 60% and 20 ml 80% Percoll (Amersham Pharmacia Biotech AB, Uppsala, Sweden), after centrifugation at 400xg for 30 minutes at room temperature, terminal polymorphonuclear leukocytes (PMNs) were obtained from the interface of 60% and 80% 5 Percoll phases, after washing twice in PBS. PMNs were suspended at a density of 1〇7 cells/ml in Hank's balanced salt solution (HBSS: Nissui, Japan) supplemented with 10 mmol concentration Na_Hepes (pH 7, 6), 0.1% BSA and stored on ice until use. 10 To test the inhibitory effect of the compound on the methylmercapto-oxime thiol-leucine-phenylalanine (fMLP)-induced superoxide production, pmNs (2xl05 cells/well) was implanted into 96 -Slot transparent bottom black plate (Cat.#3904, Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperation, social printing

Costar) HBSS, 10 millimolar Na-Hepes (pH 7.6), 0.1% BSA, pretreated with luminol (1 μg/well, Sigma) and test compound at 37 °C 1 minute, fMLP form (Cat. #4066; Peptide Institute Inc, Japan) was prepared in the same buffer at 1 μM molar concentration and prepared in a polypropylene plate (Cat. #3365, Coster). 1 micromolar fMLP stimulation After 15 minutes, chemical fluorescence (CL) was measured via FDSS-6000 (Hamamatsu Photonics), and the concentration of each compound was calculated based on the first peak of CL after about 1 minute of addition of the thorn 20 excimer. The percent inhibition is determined and the IC50 value is determined from the inhibition curve. For the conditioned leaven (〇Z) and phorbol 12-palmitate π-acetate (PMA) stimulation, the Sigina was suspended in HBSS at 9 mg/ml and at 9 to The final concentration range of 80% is at 37 °C. -48- ^^ ___ _ Heart's Zhang scale is applicable to China National Standard (CNS) A4 specification (2ι〇χ297 public Chu)~~ 200413379 A7 ------- B7 V. INSTRUCTIONS (47) The human collected serum was conditioned for 3 minutes, then centrifuged at 4 C and 500 xg for 10 minutes, and the precipitate was washed in HBSS* for rain, and finally suspended in HBSS. Concentrations between 丨 and ... mg / pen liter, using a conditioned leaven (〇z) at 53⁄4 g/ml for thorn 5 secretion, phorbol 12-palm at a concentration of 0.1 μg The phosphonium phthalate-acetate (pma) was first dissolved in DMS as a stock solution and stored frozen at -20 C. PMA was prepared from the stock solution by further diluting to a concentration of 1 〇〇 ng/ml in HBSS*. (2xl05 cells/well) implanted into a 9-slot white plate (packed anesthesia hbss, 1〇1〇耄 molar concentration Na-Hepes (pH7.6), 0.1% BSA, with luminol (1 μg/ , Sigma) and test compound were pretreated, 30 minutes after stimulation with 〇z*pMA, CL was measured via an Arv〇 counter (WaUac), the percent inhibition of each concentration of the compound was calculated and the IC5 〇 value was determined from the inhibition curve. Mononuclear cell elastase release assay IC5〇15 value]

To test the inhibitory effect of the compound on elastase release, PMNS (5xl05 cells/well) was implanted into a 96-well plate to supplement HBSS with 1 〇 millimolar concentration &-Hepes (pH 7.6), 〇_l% BSA The cells were pretreated with cytochalasin B (〇·丨微克/槽; Nakarai, japan) and 20 test compounds for 1 minute at 37 ° C and 90 μl / Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives printing tank. The cells were stimulated with 1 μmol concentration fMLP for 15 minutes at 37 ° C, and the supernatant (4 μL/well) was collected into a 384-well black plate (Packard) to measure elastase activity at room temperature. Add 10 μl of 〇·5 mmol concentration of Suc-Ala-Ala-Ala-MCA (Cat. #3133v; Peptide Institute Inc, Japan) to 384-well plate and -49- This paper scale applies to Chinese National Standard (CNS) A4 size (210x297 mm) 200413379 A7 B7 V. Inventive Note (48) Start the elastomeric reaction of the fluorescent matrix using a Waliac-Arvo counter (PerkmElmer, Boston, MA) fluorescent plate reader at 46 〇 nm 〇ex, 360 nm) measurement of fluorescence emission over 12 , minutes, measured at the initial rate of the reaction IC50 values of the compounds. 5 [Measurement of IC50 values of compounds using human PMNs in the chemotaxis assay] Freshly prepared PMNs (1·1χ1〇7 cells/ml) were supplemented with 1 〇 聚丙烯 on a polypropylene % trough plate (Cat. 33365, Costar) The compound was inoculated with the molar concentration of Na-Hepes (ρΗ7·6) and 0.1% BSA in HBSS for 10 minutes, and the cells (100 μl) were inoculated with the compound or vehicle for 30 minutes and transferred to

10 Multiwell insert (Cat. #351183; Falcon) 24w plate, add FMLP (103⁄4 micromolar, 0.5 ml) to the lower chamber of the plate and measure chemotaxis for 1 hour in a 37 C C〇2 inoculator The cells were counted using FACScan (Becton Dickinson, Franklin Lakes, NJ), the percent inhibition of each concentration of the individual compounds was determined and the IC5 〇 15 value was determined from the inhibition curve. [In the chemotaxis test method, the transfection substance is used to determine the jc 5 〇 value of the compound] (1) The Ministry of Cell Economy, the Intellectual Property Office, the employee consumption cooperation, and the social printing use of human CCR3-deformed cells, according to j·Exp. Med. 183: 2437-2448 discloses a method for constructing 20 L1.2 stable variants expressing human CCR3 via an electrochemical method (eiectr〇p〇rati〇n) to maintain human CCR3-deformed L1.2 cells at a supplement of 10%. In FCS, 100 units/ml penicillin G and 1 μg/ml streptomycin, and RP4 mg/ml Genecitin in RPMI-1640, the cells were used to contain 5 mM of the day before the chemotaxis test. Medium concentration of sodium butyrate (5χ105 cells/ml) pre-treatment-50- ♦ Paper scale applicable to China National Standard (CNS) A4 specification (21〇χ297 public) 200413379 A7 _ B7 V. Invention description (49) 20-24 The hour increases the expression of CCR3. (2) Chemotaxis test method Pre-treated cells of butyrate were suspended in chemotaxis buffer at a cell density of LlxlO7 cells/ml (Hank's solution Cat #〇59〇6 5 patrol, 20 millimoles) Concentration HEPESpH7 6, 〇1% human serum protein Cat. #A-1887 Sigma), 90 μl of cell suspension and 1 〇 microliter of compound solution diluted with chemotaxis buffer (10 times concentration of final concentration) The mixture was pre-incubated at 37 C for 1 min, and a mixture of cells and compounds was added to the upper chamber of the 24-tank chemotaxis chamber (TransweiiTM, Cat #342i, c〇star 10 pore size 5 μm) for chemotaxis. Buffer dilution 〇·5 升 10 nanomolar concentration Human re-recombinant etaxin (Cata #23209, Genzyme Techne) solution was added to the lower layer of the chemotaxis plate, then at 37 ° C The chemotaxis was carried out in the 〇2 incubator. After 4 hours of brothing for 4 days, the cells were counted by FACScan (Becton Dickinson), and the percent inhibition of each concentration of the compound was calculated and the IC50 value was determined from the inhibition curve. . [Mice fMLP-induced pleurisy model] Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative Printed 7-week-old BALB/c female mice into 3 groups of non-treatment group, vehicle group and treatment group, in the treatment group The mice were injected intravenously with different doses of 20 compounds of the invention, and the mice in the vehicle group were injected with 10 〇/〇.

Cremophor EL (Nacalai Tesque) in saline, after 3 minutes of treatment, 3.3% DMSO in PBS containing 1 mg/mouse fMLP solution was administered intraplevally to the vehicle group and the treated group of mice, fMLP - After 4 hours of injection, the mice were killed and the pleural cavity was washed twice with 2 ml of PBS -51- This paper scale was applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200413379 A7 B7 V. DESCRIPTION OF THE INVENTION (5〇) The pleural fluid was collected, the total number of cells per ml of pleural fluid was counted using a red blood cell meter, and the cells of the pleural fluid were determined by counting a minimum of 200 cells from the Giemsa-stained cytospin section preparation. Differences were statistically analyzed using Student's t-test 5 of the paired data or variation analysis of the Dunnett's Post test using the GraphPadPRISM for Windows version 2.01. Based on practical factors, the compounds are classified into the following active species:

Intratube I 〇 A (= or <) 0.1 micromolar concentration < B (= or <) 〇 · 5 micromolar concentration < C (= or <) 2 micromolar concentration < D The compounds of the invention also show strong activity in vivo. 10 (dec.) in the table below indicates decomposition. Example Μ : (Ζ)-2-(8,9-Dimethoxy-2,3-dihydroimidazo[l,2-c]oxazolium-5-yl)-1-(3-pyridyl) Ethyl alcohol (1) 3-keto-3-(3-pyridyl) propionate decyl 15

〇v^+ 1 Y Me〇OMe 智慧 Ministry of Economic Affairs Intellectual Property Bureau staff consumption cooperation, the company printed hexamethyldiazine nitrogen in the benzene benzene 5 5 molar concentration solution (22 mil 20 liters, 11 mM The ear was mixed with tetrahydrofuran (5 ml), the mixture was cooled to -78 ° C, and added to a mixture of 3-78 hydrazine in a mixture of -78 hydrazine (1.0 g, 8.26 mmol). A solution of tetrahydrofuran (5 ml), the mixture was allowed to warm to room temperature and stirred for 3 hr, then the mixture was cooled to _78 C, then dimethyl carbonate (L2 mL, 14·3 mmol-52- paper) was added dropwise The scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

5, the invention description (51) ear, the resulting solution was warmed to room temperature and stirred overnight, by adding 1 to the bright concentration of aqueous HCl solution was quenched and extracted with ethyl acetate three times, the combined organic layer with water and It was washed with brine, dried over MgSO4, EtOAcjjjjjjjjjjjjj (3-pyridyl) propionic acid 曱 cool (1.0 g, 68% yield) of oil. (2) 2-(4,5-Dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline

2-Amino-4,5-dimethoxybenzonitrile (5.0 g, 28 mmol) was added to ethylenediamine (7.9 g, 131 mmol) at room temperature to warm the resulting solution. To 40 ° C, and add a catalytic amount of diphosphorus pentoxide (50 mg), 15 the mixture was sent to 80-90 ° C, and stirring was continued overnight, the reaction mixture was diluted with water, and the resulting precipitate was collected by filtration to obtain Solid of 2-(4,5-dihydro-1H-imidazol-2-yl)-4,5-dimethoxyaniline (5.1 g, 8% yield). (3) (Z)-2-(8,9-Didecyloxy-2,3-dihydroimidazo[l,2-c]oxazoline-5-20-yl)-1-(3-port Pyridyl)ethanol

-53- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm)

200413379 A7 B7 V. INSTRUCTIONS (52) 2-(4,5-Dihydro-111-imidazol-2-yl>4,5-dimethoxyaniline (0.15 g, 0.68 mmol) and 3 a mixture of keto-3-(3-pyridyl)propanoate (0.20 g, 1.12 mmol) was stirred at 155 ° C for 1 hour and chromatographic on silica gel (dichloromethane / methanol) , 2 5 /1) Purification reaction Mix 5 to obtain (Z)-2-(8,9-dimethoxy-2,3-dihydroimidazo[l,2-c]oxazoline-5- a yellow solid of 1-(3^pyridinyl)ethanol (66.9 mg, 28% yield). m.p.: 275.

10 PI3K-yS inhibitory activity in vitro: C In vitro PI3K-T inhibitory activity: A b-NMR (500 MHz, DMS〇-d6) (5: 3·79 (3H, s), 3.88 (3H, s ), 3.98-4.08 (4Η,m),5·63 (1Η,s),7·13 (1Η,s), 7.24 (1Η,s), 7.50 (1H,dd,J=4.7, 7.8 Hz), 8·27 (1H, dt, J=1.6, 7·8 Hz), 15 8·67 (1H, dd, J=1.6, 4.7 Hz), 9.13 (1H, d, J=1.6 Hz), 13·9 (1H, bs) 〇Example 1-2: Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed (Z)-2-(8,9-Dimethoxy-2,3-diimidazo[1,2- c]oxazoline-5-yl)-1-(3-pyridyl)ethanol hydrochloride

-54- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Α7 Β7 V. Description of invention (53) at (Z)-2-(8,9-dimethoxy-2,3 - Dihydroimidazo[1,2-c]oxazolium-5-yl)-1-(3-pyridyl)ethanol (16.8 mg, 0. 05 mmol) in dioxane (15 mL) 6 equivalent of HCl aqueous solution (0.05 ml) was added to the solution at room temperature, and after stirring for 30 minutes, the mixture was dried under reduced pressure to give (Ζ)-2-(8,9-dimethoxy-2). , 3-Dihydroimidazo[l,2-c]oxazoline-5-yl)-1-(3-pyridyl)ethanol hydrochloride (18.5 mg, EtOAc). Melting point: >300 ° C Mass spectrometry: 351

10 PI3K-y5 inhibitory activity in vitro: C In vitro PI3K-T inhibitory activity: A iH-NMR (500 MHz, DMSO-d6) (5: 3.88 (3H, s), 4.00 (3H, s), 4.22 (2Η,t,J=9.1 Ηζ), 4.55 (2Η,t,J=9.1 Ηζ), 6.21 (1Η,s), 7.60 (1H,s),7·66 (1H,dd,JN4.7, 8.2 Hz), 7.90 (1H, s), 8.47 15 (1H, d, J = 8.2 Hz), 8.79 (1H, d, J = 4.7 Hz), 9·28 (1H, s) 5 14.9 (lH, Bs). Example 1-3: Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printing 2-[7-Methoxy-8-(methoxymethoxy)-2,3-dihydroimidazo[1,2 -c]oxazolium-5-yl]-1-pyridin-3-ylvinyl alcohol 20 (1) 4-methylindol-2-yloxy-3-nitrophenyl acetate

η η

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Inventive Note (54) The method disclosed by US Patent 4287341 or J. Chem. Soc. 376 (1948), vanillyl acetate 5_00 The title compound was obtained as a yellow solid (yield: 43.6%). iH-NMR (500 MHz, DMSO-d6) δ: 2.40 (s, 3H), 3.87 (s, 3H), 5 7.75 (d, 1H, J = 8.4 Ηζ), 7·94 (d, 1H, J = 8.4 Ηζ), 9·90 (s, 1H). (2) 4-Hydroxy-3-methoxy-2-nitrobenzaldehyde 10 Η

〇

Stir a mixture of 4.54 g (19.0 mmol) of 4-methylindenyl-2-methoxy-3-nitrophenyl acetate and 5.24 g (37.9 mmol) of potassium carbonate in 40 ml of decyl alcohol at room temperature. 2 hours, the reaction mixture was poured into water, acidified by 1 I concentration of HC1 solution and extracted to Ac〇Et, the organic layer was printed with brine 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative 20/month wash, via MgS〇4 Dry, filter and evaporate the solvent, and the residue was washed with n-hexane to give the title compound 3·6 g of a white solid, yielding 96.3% 〇(3) 4-hydroxy-3-decyloxy-2-nitrobenzonitrile

〇Me OMe in 4-hydroxymethoxy-2-nitrobenzaldehyde 14.5 g (73.5 mmol) in a mixture of 28% 28% ammonia solution and 15 ml of tetrahydrofuran -56- This paper size is suitable for X 297 200413379 A7 B7 V. Description of the invention (55 iodine 22.4 g (88·2 mmol) and stirred at room temperature overnight, the reaction mixture was concentrated in vacuo and the residue was acidified with 2 eq. The organic layer was washed with EtOAc (EtOAc) EtOAc (EtOAc m. 4-(methoxymethoxy)_2_nitrobenzonitrile 10 15

HO

NO. OMe

CN

MeO 〇

NO, OMe

CN Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed 4-amino-3-methoxy-2-stone succinyl nitrile i. gram, chloromethyl decyl ether 0. 47 ml (6·18 mmol) Ear) and potassium carbonate 3.56 g (25 8 mmol) in a mixture of Ν, Ν-dimethylformamide 10 ml at 5 〇. The mixture was poured into water and poured into water and extracted with diethyl ether. The organic layer was washed with brine, dried over EtOAc, filtered and evaporated. The title compound i 〇 3 ^ solid was obtained, yield 83.5%. ..., color (3) 1 amine I methoxy winter (methoxy methoxy) afternoon ride 20

MeO 〇

CN NO, OMe

MeO^^〇

CN NH, OMe -57-

200413379 A7 B7 V. INSTRUCTIONS (56) In a solution of 50 ml of ethanol and stirring at room temperature under a hydrogen atmosphere for 8 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo, EtOAc (EtOAc/EtOAc) The title compound was obtained as a white solid (yield: 53.9%). 5 (6) [6-(4,5-Dihydro-1H-imidazol-2-yl)-2-methoxy-3-(methoxymethoxy)phenyl]amine

2-Amino-3-methoxy-4-(methylindenylmethoxy)benzonitrile 475 mg (2.28 mmol) and pentasulfide 254.0 mg (0.11 mmol) in ethylenediamine 2.75 g of the solution was stirred at 120 ° C overnight, the reaction mixture was cooled to room temperature and poured into water, and the precipitate was collected and washed with water to give the title compound 293 mg of white solid. (7) 3 - mercapto-3 - (^ than bite-3 -yl) propionate

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed in a suspension of nicotinic acid 5.00 g (40·6 mmol) in tetrahydrofuran 50 ml, adding 9.76 g of carbonyl diimidazole at 5 ° C (60.9 m paper scale) Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379

Mohr) and mix at room temperature! In the other flask, 64 grams (48.7 millimoles) and malonic acid vinegar salt ίο"? Grams (60.92 ^ jMi jsi ληηλ. & 士,斗) in a suspension of 50 ml of tetrahydrofuran at 5 ° C: in this suspension, add the above imidazole solution at room temperature and stir for 5 ^ The reaction was quenched by adding water and extracted to an ethyl acetate-ethyl layer. The organic layer was washed with brine, dried over M§S〇4, filtered, and filtered, and the mixture was filtered. (JiJi/AcOEt=2/l The title compound was obtained as a pale yellow oil (yield: 49.5%). (8) 2-[7'Methoxy·8,(methoxyoxyloxy)-2,3·diaza[1,2-dicarboxy]〇♦林_5·基]小吼灯基乙Alcohol 15

Me〇

〇Me

Tt • i Ministry of Economic Affairs, Intellectual Property and Consumer Cooperatives Printing - [6·(4,5-Dihydro·1Ή_imidazole·2·ylmethoxy_3_(methoxymethoxy)amine oxime.31克(5·2〇mole) and 3-_yl-3-decapyridinium+yl) Propionic acid B.S. 1.GG (5.2Q millimolar) in toluene 3 () ml solution reflux 20 The collected material was collected and washed with (10) to give the title compound (5) g of a yellow solid with a yield of 76.9%. Melting point: 215-216X: Mass spectrum: 381 In-tube PDK-million inhibitory activity: -59^ Zhang scale standard family standard (CN^ ^^· (210 χ 297 public) 200413379 A7 B7 V. INSTRUCTIONS (5 〇 PI3K- τ inhibitory activity in vitro: b iH-NMR (500 MHz, CDC13) 5 : 3.54 (s, 3H), 3.95 (t , 2H, J=9.5 Ηζ), 4·08 (s, 3H), 4.22 (t, 2H, J=9.5 Ηζ), 5·30 (s, 2H), 5.38 (s, 1H), 6·98 ( d, 1H, J = 8.8 Hz), 7.37 (dd, 1H, J = 8.0 Hz, 5 4.9 Hz), 7·64 (d, 1H, J = 8.8 Hz), 8.21 (dt, 1H, J = 8.0 Hz) , 1.7

Hz), 8.67 (dd, 1H, J=4.9 Hz, 1.7 Hz), 9.09 (d, 1H, J=1.7 Hz), 13.75 (s, 1H) 〇Example 1-4 : 5-(5-Hydroxy-2 -pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[10,2-c]oxazolyl-8-ol hydrochloride

2-[7-Methoxy-8-(methoxymethoxy)_2,3-dihydroimidazo[l,2-c]oxazoline-5-yl]-1-pyridine_3_ Vinyl alcohol (Example 1-3) 1.52 g (4.00 mmol) of a suspension of 4 equivalents of HCl 1 30 ml and water 20 〇·3 ml in l,4-dioxime was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. Melting point: 245 ° C Mass spectrometry: 337 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -60- This paper scale applies Chinese National Standard (CNS) A4 specification (21〇X 297 mm) 200413379 A7 B7 V. Invention description (59 In vitro PI3K-/3 inhibitory activity: c In vitro PI3K-T inhibitory activity: a b-NMR (500 MHz, DMSO-d6) (5: 3.97 (s, 3H), 4.22 (dd, 2H, J = 12.3) Hz, 9·0 Hz), 4·43 (dd, 2H, J = 12.3 Hz, J = 9.0 Hz), 6·17 5 (s, 1H), 7·10 (d, 1H, J = 9.0 Hz) , 7.71 (dd, 1H, J=7.7 Hz, 4.7

Hz), 7.98 (d, 1H, J = 9.0 Hz), 8.57 (br d, 1H, J = 7.7 Hz), 8.82 (dd, 1H, J = 4.7 Hz, 1.4 Hz), 9·34 (d, 1H) , J = 1.4 Hz), 11.79 (s, 1H), 14.60 (s, 1H). Example 1-5: 10 4-{[5-(2-Hydroxy-2-indan-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[1,2-c] Methyl oxazoline-8-yl]oxy}butyrate

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperative of 5-(2-Pyryl-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydro-flavor[1,2 -C]°Chawa Sigmalin hydrochloride (Example I—#) jo·#mg20 (〇·14 house Moule), methyl chlorobutyrate 22.2 mg (0.16 mmol) and potassium carbonate 186.9 mg (1_35 mmol) of a mixture of hydrazine and hydrazine-dimethyl decylamine in 1 ml at 12 (TC for 4 hours, the reaction mixture was poured into water and extracted to a chloroform, and the organic layer was washed with brine. Drying through MgSCU, filtering and evaporating the solvent, and washing the residue with diethyl ether -61- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 200413379 A7 ___ B7 V. Inventive Note (6〇) 35.0 mg of a yellow solid, yield 59.3%. Melting point: 199-200. 〇 Mass Spectrum: 437

In vitro PI3K-cold inhibition activity: c 5 In vitro PI3K-7" Inhibitory activity: A h-NMR (500 MHz, DMSO-d6) 5 : 2.20 (five peaks, 2H, J = 7.1 Ηζ), 2.58 (t, 2H, J = 7.09 Ηζ), 3·71 (s, 3H), 3.94 (t, 2H, J = 9.5 Hz), 4.06 (s, 3H), 4.15 (t, 2H, J = 7.1 Hz) , 4·21 (t, 2H, J = 9.5 Hz), 5.38 (s, 1H), 6.76 (d, 1H, J = 8.8 Hz), 7.37 (dd, 1H, J = 8.2 10 Hz, 5.2 Hz), 7.65 (d, 1H, J = 8.8 Hz), 8.21 (dt, 1H, J = 8.2 Hz, 2.1 Hz), 8.67 (d, 1H, J = 5.2 Hz), 9·09 (s, 1H), 13.70 (s5 1H). Example 1-6: Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Print Example 3-4; 4-{[5-(2-Hydroxy-2-indan-3-ylvinyl)-7-decyloxy-2 , 3-dihydroimidazo[l,2-c]oxazoline group]oxy}butyric acid 15

4-{[5-(2-Hydroxy-2-pyridin-3-ylvinyl)-7-decyloxy-2,3-dihydroimidazo[l,2-c]oxazolium-8- Methyl]oxy}butyric acid methyl ester (Example 1-5) 20.0 mg (0.05 mmol) in a solution of 1 equivalent of Li〇H solution 0.1 ml and ethanol 1.0 ml at room temperature overnight, mixing the reaction -62 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 10 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (61) physical use 1 when the concentration of HC1 solution is neutralized The residue was concentrated in vacuo. EtOAc m. Melting point: 257-258. (: Mass spectrometry: 423 in vitro ΡΙ3Κ-cold inhibition activity: β In vitro PI3K-r inhibitory activity: a H-NMR (500 MHz, DMSO-d6) (5: 2.02 (five peaks, 2H, J=6.2)

Hz)5 2.45 (t? 2H5 J=6.2 Hz), 3.94 (s, 3H), 3.98 (br t, 2H, J=8.5

Hz), 4·06 (br t, 2H, J = 8.5 Hz), 4.14 (t, 2H, J = 6.2 Hz), 5.67 (s, 1H), 6.97 (d, 1H, J = 8.7 Hz), 7.49 (dd, 1H, J = 8.2 Hz, 4.4 Hz), 7.57 (d, 1H, J = 8.7 Hz), 8.29 (d, 1H, J = 8.2 Hz), 8.67 (d, 1H, J = 4.4 Hz) ), 9.14 (s5 1H)5 12.15 (s5 1H)5 13.76 (s9 1H) 〇Example 1-7 : 4-{[5-(2-Hydroxy-2-pyridine-3-ylvinyl)-7-oxime Oxy-2,3-dihydroimidate[1,2-c]oxazolium-8-yl]oxy}butyrate 20

HCI 4-{[5-(2-hydroxy-2-pyridin-3-ylvinyl)-7-methoxy-2,3-dihydroimidazo[l,2-c]oxazolium-8 -基]oxy}butyric acid (Example 1-6) 4.0 -63- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention (62 10 15 mg (9.5 m) The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether. The title compound was evaporated. Melting point: 249-251 ° C Mass spectrometry: 423 in vitro PI3K-call inhibition activity: b In vitro PI3K-r inhibitory activity: A iH-NMR (500 MHz, DMSO-d6) 5 : 2·06 (five peaks, 2H, JN7.3 Ηζ), 2.46 (t, 2 Η, J = 7.3 Ηζ), 4.01 (s, 3 Η), 4.24 (t, 2 Η, J = 9.0 Hz), 4.29 (t, 2H, J = 7.3 Hz) , 4.45 (t, 2H, J = 9.0 Hz), 6· 18 (s, 1H), 7·36 (d, 1H, J = 9.1 Hz), 7.70 (dd, 1H, J = 7.9 Hz, 5.0 Hz) , 8.14 (d, 1H, J = 9.1 Hz), 8.56 (br d, 1H, J = 7.9 Hz), 8.82 (br d, 1H, J = 5.0 Hz), 9.34 (s, 1H), 12.34 (s, 1H), 14.5 7 (s, 1H). Example 1-8: 2-[7-Methoxy-8-(4-moffin-4-yl-4-ketobutoxy)_2,3-dihydroimidazole [l,2-c]carbazole π-lin-5-yl]-1-pyridin-3-yl vinyl alcohol loading line Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20

In the Chinese standard (CNS) A4 of 4-{[5-(2-3⁄4 base-2-mouth ratio -3-ylvinyl)>7-decyloxy-2,3--64- Specifications (210 X 297 public) 200413379 A7 B7 V. Description of invention (63) Dihydroimidazo[l,2-c]oxazoline-8-yl]oxy}butyric acid (Example 1-6) 20.0 mg (0.044 mmol), 19.0 mg (0.22 mmol) and N,N-diisopropylethylamine 0.038 ml (0.22 mmol) in hydrazine, hydrazine-dimethylformamide 2.0 PyBOP ((1Η-1,2,3-benzene-5-triazol-1-yloxy)(tripyrrolidin-1-yl)sulphonium hexafluorophosphate) was added to a solution of 34.0 mg (0.065 mmol) The mixture was stirred overnight at 80 ° C. After cooling to room temperature, the reaction mixture was poured into water, and the crystals were collected and washed with water to give the title compound 13.0 mg of white solid, yield 60.7%. Melting point: 234-235 ° C 10 Mass spectrometry: 492

In vitro PI3K-/3 inhibitory activity: B In vitro PI3K-r inhibitory activity: A W-NMR (500 MHz, DMSO-d6) 5 : 2.03 (five peaks, 2H, J = 6.6 Hz), 3.46 (m, 4H), 3.56 (m, 4H), 3.96 (s, 3H), 3.99 (br d, 2H, 15 J = 8.2 Hz), 4.05 (br d, 2H, J = 8.2 Hz), 4.15 (t, 2H, J=6.6 Hz), 5·66 (s,1H), 6.98 (d, J=8.8 Hz), 7.50 (dd, 1H, J=7.7 Hz, 4.7 Hz), 7.57 (d, 1H, J=8.8 Hz) ), 8.29 (br d, 1H, J = 7.7 Hz), 8.67 (br d, 1H, J = 4.7 Hz), 9.14 (s, 1H), 13.76 (s, 1H). Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives; 4 A ·! The compounds of Examples 1-9 to 1-20 210 were synthesized according to a similar method to Examples 1-1 to 1-8. -65- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (64) Table 1 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention (65 Example h No. 1-13 Structure Molecular weight MS (M+1) mp 尔 ―

N 364,41 365 267-268

A h3c Ο 1-14

N H3 (T 0 h3c .0

HO

378,43 379 252-253

A • I i

N

1-15

390,45 391 254(dec.)

B Order 1-16 H〇, Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs 1-17 〇

.0 h3c, ho

C!H H〇, /^ 〇

HX 380,41 416,87 381 381 264-265 215(dec.)

A

A ·! This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) -67- 200413379 A7 B7 V. Invention description (66) -68- This paper scale applies to China National Standard (CNS) A4 specification (210x297 MM)

Real column No. Structure: Molecular weight MS (M+l) mp 1-18 N^ H3V in the tube.丫,义 f丄A 叫外0 h3c-° ηο^0ν 450,50 451 184-186 B 1-19 Ν--λ ?Η3 ίΡΤ^ΐ h3cx〇HO Person Cy 407,48 408 183-184 B 1- 20 h3c/〇H〇l[fjN 447,54 448 162-163 B 1-21 〇^. City H3C/〇433,51 434 204-205 A 1-22 丫〇H3C/〇430,85 395 240(dec.) A Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 200413379 A7 B7 V. Invention Description (67) Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

―研号号Μ" -·- MS (M+l) mp 詨 tube _ molecular weight 1-23 ° h3c-° ho-V^n 393,41 394 297-298 A 1-24 fYQ C,H 0 η, 429,87 394 235(dec.) A 1-25 0 H3C〆0 443,89 408 240(dec.) A 1-26 h cih Ύ 丫, ^ 〇h3c-° ΗΟ^γ^Ν 471,95 436 245 (dec.) A 1-27 〇H〆0 421,46 422 241-242 A -69- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention (6〇 Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

rfW No. Structure: MS (M+l) mp Intratube molecular weight 1-28 〒H3 cih Η3〇^γ-〇ν^Λ 0 Η, 457,92 422 205(dec.) A 1-29 Νν ίΡΤ^Ι 〇 Η, ΗΟ人 γ^Ν u 463,50 464 234-235 A 1-30 Ογ-οΧ^ C,H 0 H3C〆0 Η〇/ΐΓ^Ν u 499,96 464 240-241 A 1-31 CIH 0 Η〆0 ΗΟ^Ί^Ν 537,98 502 230-231 B 1-32 JO h3c/〇h 391,43 392 >285 A -70- This paper scale applies to China National Standard (CNS) A4 specification (210x297 PCT) 200413379 A7 B7 V. Description of invention (69 Example number structure molecular weight MS (M+l) mp in vitro 1-33

/〇 H3C Η7(Τ 丫

CIH

427,89 392 273

A 1-34

Ν 373,42 374 >285

A.〇 1-35 a:>

CIH

H3 (T ho 409, 88 374 270

A 1-36 449, 51 450 197

A Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

N—This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 A7 B7 V. Invention Description (70) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

Example · No. Structure 'Molecular Weight MS (M+l) rap Tube Λ 1-37 〇~. Ν^\ Λ> Ά ΗΟ^ CIH 广Ν 485,97 450 215 A 1-38 η c,H 〇0^° H〇UA, Η 3 543,03 507 260 A 1-39 NV Q 433,51 434 217 B 1-40 ηΎ Ον~. Λ) Η〇〆 CI; Η 469 469,98 434 256(dec.) B 1-41 Ν\ CIH .cApCl ο~. ΗΛα人 Η 3 527,03 491 271 A -72- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (7i) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-73- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (72) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-74- 埤 ii·! This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention (73 Example No. Structure Molecular Weight MS (M+1) In-tube

CH, 400, 87 365 260 (dec·)

B 1-51

443,89 408 275-280

B 1-52

379,42 380 321-325

B ·: i tt I I I I I I I I ii I 1 I I:: 3 5 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed

CH3

393,45 394 195-198 B This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) -75- 200413379 A7 B7 74 V. Invention Description - Example No. 1 Molecular Weight MS (M+1) mp Test Inside the tube

5 -5

N-

N

Cl 384,83 385 283 Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative

This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm). 200413379 A7 B7 5 7 r\ Ming Ming Λ5 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

CIH CIH

CH,

CK molecular weight 355,42 391,88 384,46 420,92 MS (M+l) 356 356 385 385 mp 250 266-268 292 268-271

B

B

A

A ·: i count I I I I I I I I I This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -77- 200413379 A7 ____ B7 V. Description of invention (76)

400,87 365 285 A 63

CIH

% tl Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Clothes

-78-, 绵 This paper size applies to China National Standard (CNS) A4 specification (210x297 public) 200413379 A7 B7 V. Invention Description 77 Example No. Structure Molecular Weight MS (M+1) mp Sene 1-66

HX

403,44 404 280

B 1-67

HX

439,91 404 >285

B 1-68

320,35 321 275

A 1-69 356,81 321 285

A Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

^ -- -I

α

C N丨 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention (78 Example number structure Molecular weight MS (M+l) mp In-tube 1-70 N-

N CIH

308,32 309 218

A 1-71 Ν-

Ν CIH

344,78 309 303

B 1-72

324,77 325 210(dec.)

B Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (79) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-81-

It I I I I I 1 1 I I I Qin i I I I I This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 A7 B7 V. Invention Description (80) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

This paper scale applies to China National Standard (CNS) A4 specification (210x297 public) 200413379 A7 ____ B7 V. Invention Description (Si) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-83- This paper size applies to China National Standard (CNS) A4 specification (210x297 public) 200413379 A7 B7 V. Description of invention (82) Example No. Structure Molecular Weight MS (M+1) mp In-tube 1-86

377,45 378 186-187

B 1-87 391,48 392 235(dec.)

B

C-N H3C

TT I I 1 I I I 1 I 1 Qin i I I I I Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing △

4 8 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (83 Real #编号 1-90 1-91

HO structure

N-

〇

N

Molecular weight MS (M+1) mp in vitro 420,47 350,38 421 351 222-223 211-212

A

B 1-92 H〇, N-

364,41 365 203-205

A 1-93 348,36 349 225-226

B N-

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

T

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention (84) Example·No. Structure Molecular weight MS (Μ+1) mp In-tube 1-94 〇〇' N-

N

, N

HO

N

375,43 376 282 Β 1-95 411,89 376 >300 Β

Ν Ν Ο Η〇

1-96

Ν CH, 432,49 433 269(dec.)

A loaded 1-97

CIH

468,95 433 246

A line Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative ο

3 CH X NH This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (85) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-87- ·; 4tj ii•i This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Ming said Mingfa Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed clothing

Example ' Numbered Structure Molecular Weight MS (M+l) mp In-tube 1-102 X H0 iXx Eight ch3 482,97 447 238(dec.) B 1-103 OuD from 501,04 466 257 B M04 η H3C^Nv^ HO ^Nj^N 424,94 389 288 B 1-105 " UA, 445,53 446 292(dec.) B M06 nr^A aH ηΛ〇1 person 481,99 446 280(dec.) B 88- 200413379 A7 B7 V. Description of Invention (87) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

Example No. Structure # Molecular Weight MS (M+l) mp In a test tube 1-107 .rV9 Η 427,51 428 207 A 1-108 C!H Η,0 ηΛ0} Η 463,97 428 >300 B 1-109 Cj ^ Η0 υ h3c 416,49 416 A 1-110 Ν*—\ CIH η3〇.νΛ^νΑ η〇Η〇Λα> Η 438,92 403 231 (dec.) B 1-111 OXCa Η〇人丫^Ν 389,46 390 204 B -89- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (88) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-90- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 V. Invention description (89) A7 B7

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

-91-

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 _;___B7 V. Invention description (9〇)

-92- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (9i) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-93- Install tt I I I I I I I I I ά I I I I!! This paper scale applies Chinese National Standard (CNS) A4 specification (210x297 mm) 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print A7 _____B7 V. Invention description (92)

-94- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (93 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm). il ·! 200413379 A7 B7 V. Description of invention (94) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs

-96- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention (95 Example · Number Molecular Weight MS (M+l) mp 1-141

291,31 292 233-235

B 1-142 Ν-Λ

CIH 327,78 292 217-222

B ❿

ΝHO

Packing 1-143

279,30 280 192

B 1-144 315,76 280 >300

B

Line I Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed α α

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (96—W No. Structure Molecular Weight MS (M+1) mp In-tube 1-145

279,30 280 155-156

B 1-146

295,37 296 193

A loaded 1-147

331,83 296 >300

A meter 1-148

295,37 296 182-183

B Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed α N.

This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (97) Example No. Structure Molecular Weight MS (M+1) mp 1-149

S 331,83 296 >300

A 1-150

278,32 279 247

B 1-151

278,32 279 247-249

A 1-152 280,29 281 148

B Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing a

〇

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (98) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-100- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm). Transfer ii d 200413379 A7 B7 V. Invention Description (99) This paper scale applies Chinese National Standard (CNS) A4 specification (210x297 mm). )

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

200413379 A7 B7 V. Description of Invention (101) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (1〇2) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-104- ·; 4 ii m This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (103) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-105- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (1〇4) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-106- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (1〇5) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-107- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 A7 _____ B7 V. Invention description (i〇6) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-108- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (107) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-109- The paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (1〇8) Ministry of Economic Affairs Intellectual Property Bureau Employee Consumption Co., Ltd. Printing Example Number Structure Molecular Weight MS (M +l) mp in a test tube 1-194 ^ 〇Me HO-Sr^N u 434,50 435 233-234 A 1-195 N\ 〇Me H0 lQ 375,39 376 284-285 A 1-196 [TN 0Me HCT ^^N 418,42 419 229-231 A 1-197 nn 〇Me h〇人454,88 419 217-218 A 1-198 HC, ° (10) H.乂^N u 528,01 492 215-216 A ' -110- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description 109 No. Structure Molecular Weight MS (M+1) Mp test tube 1-199

Me〇

436,47 437 178-179

A 1-200

HCI 430, 85 395 286 (dec.)

B Η〇"^0

1-201

398,85 363 273(dec.)

A 1-202 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1-203

Me

413,87 405,46 378 406 285(dec.) 228

B

B This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (no) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

倒倒·· No. MS (M+l) mp Intratube molecular weight 1-204 N—^ 447,50 448 262 C 1-205 Ν— 445,53 446 246 B 1-206 ΝV h〇y---XXa hc , 0 ηΛ〇427,89 392 267 A 1-207 γ-ΝΛ hc, 〇0 U 425,92 390 259(dec.) B 1-208 Ν—Λ 9V 〇0 H0 UA _^__ 446,51 447 253 (dec.) B This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -112- 200413379 A7 B7 V. Invention Description (111) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -113-

Im. Structure MS mp Intratube numbered molecule Ϊ (M+l) 1-209 - 〇ο Η〇ΛαΛ Η 482,97 447 >260 B 1-210 HC! V ηΛ〇:ν》 OH VH 464,96 429 >300 — A This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention (112) Example 2-1: N-(2,3-dihydroimidazo[l ,2-c]oxazolium-5-yl)nicotinium amide (1) 2-(4,5-dihydro-1H-imidazol-2-yl)aniline

H,N

2-Aminobenzonitrile (9.00 g, 76.2 mmol) was added in small portions at 0 ° C to ethylenediamine (25.5 mL, 381 mmol) and stirred, and 10 phosphorus pentasulfide (200 mg, After 0.900 mmol, the mixture was stirred at 100 ° C. After cooling to 0 ° C, the reaction was diluted with water, and the obtained white precipitate was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure. -(4,5-Dihydro-1H-imidazol-2-yl)aniline (10.0 g, 81% yield). 15 (2) 2,3-Dihydroimidazo[l,2-c]oxazolium-5-ylamine bromide

BrH

Br Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20 in 2-(4,5-two-rat-1Η-σm-Sial-2-yl)aniline (5.00 g, 31.03⁄4 mol) at 85% sterol (60 Cv) Cyanogen bromide (3.61 g, 34.1 mmol) was added portionwise to a suspension at 0 ° C, and the mixture was stirred at room temperature overnight. After the mixture was concentrated under reduced pressure, the obtained precipitate was collected by filtration. The pale green solid was washed with water, methanol and diethyl ether in sequence, and the Chinese National Standard (CNS) A4 specification (210x297 mm) was applied at the minus-114- paper scale. 200413379 A7 B7 V. Invention Description (113) Drying This gave 2,3-dihydroimidazo[l,2-c]indazol-5-ylamine bromoate (4.94 g, 60% yield). (3)>^(2,3-dihydroimidazo[1,2-(:]oxazolium-5-yl)nicotinamide

10 in 2,3-dihydroimidazo[l,2-c]oxazoline-5-ylamine bromide (500 mg printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, 1.87 millimoles) Nicotinic acid (346 mg, 2.81 mmol) was added to a suspension of hydrazine, hydrazine-dimethyl decylamine (25 ml) at room temperature in the presence of benzotriazol-1-yl-oxy-para-hydrazine. Pyridyl-squamous hexafluorophosphate (1.46 g, 2.81 mmol) and hydrazine, hydrazine-diisopropylethylamine (1.30 ml, 7.49 mM 15 mol), and the mixture was heated at 80 ° C for 4 hours. After cooling to room temperature, the mixture was quenched with saturated aqueous NaHCO3, and the obtained precipitate was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give N-(2,3-dihydroimidazo[1, 2-c]oxazolium-5-yl)nicotinamide (450 mg, 83% yield). 20 Melting point: 238-239 ° C (decomposition) Mass spectrometer · · 292

PI3K-/3 inhibitory activity in vitro: B In vitro PI3K-T inhibitory activity: A ^-NMR (300 MHz? DMSO-d6) ά : 4.00-4.11 (2H? m)5 4.11- -115- This paper size applies China National Standard (CNS) A4 Specification (210x297 mm) 200413379 A7 B7 V. Invention Description (m) 4.21 (2H, m), 7_29 (1H, ddd, J=3.〇, 5.3, 7.9 Ηζ), 7· 52 (1H, dd J=4.9, 7.9 Hz), 7.57-7.66 (2H, m), 7·89 (1H, d, J=7.9 Hz), 8.42-8.48 (1H, m), 8.73 (1H, dd , J=i.9, 4.9 Hz), 9·32 (1H, d, J=ll Hz), 12.36 (1H, s). 5 Example 2-2: N-(2,3-dihydroimidazo[i,2-c]carbazole-based I-base amide hydrochloride

Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed on N-(2,3-dihydroisoxazo[i,2_c]n- quinazoline-glycolyl) in an alkali amide (150 oz, 0.515 mmol) Tetrahydrofuran (4 ml) was in hydrazine. Add 4 liters of hydrogen acid solution (2 ml, 8 Torr) of hydrazine in the 15 liters of hydrazine, and mix the mixture at room temperature for one hour, and then swell under reduced pressure. The obtained residue was triturated with diethyl ether, and the obtained precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give a mixture of (2, indane dihydroimidazo[1,2-c]oxazolidine_5_ Base) Nicotine guanamine hydrochloride (192 mg, 20 basis weight). Melting point: 289 ° C (decomposition) Mass spectrometry: 292 In-vitro Π 3Κ-/3 inhibitory activity: b M3K-r inhibitory activity in vitro: a -116- This paper scale applies to Chinese national standards (CNgI^^21〇χ297) 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (115 ) ^-NMR (300 MHz? DMSO-d6) 5 : 4.18-4.30 (2H? m)5 4.54-4.65 (2H, m) , 7.56-7.65 (1H, m), 7.88 (1H, dd, J=4.9, 7.9 Hz), 7.97-8.10 (2H, m), 8·64 (1H, d, J=7.9 Hz), 8.80 (1H , d, J = 7.9 Hz), 8.95 (1H, dd, J = 1.5, 5·3 Hz), 9·43 (1H, d5 J=ll Hz), 5 12.7-13.3 (1H, br). Example 2-3: 6-(Acetylamino)-N-[8-(morpholine-4-yl)-2,3-dihydroimidazo[l,2-c]oxazolium-5- Nicotinamide amide (1) 4-(morphine-4-yl)-2-indole sylvestris 10 15 20 η

κ 〇0 Λ:: a mixture of 2.20 g (21.75 mmol) of 2,4-dinitrobenzonitrile and 5.7 ml (66.0 mmol) of N,N-dimercaptocarboxamide in 20 ml of 2,4-dinitrobenzonitrile The mixture was stirred at room temperature for 20 hr. (2) 2-Amino-4-(morphine-4-yl)purine 〇0

XXI 〇0

XXI in tin chloride (Π) dihydrate (56.7 mmol) in concentrated HC1 40 ml •117-

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7

10 The ice-bath cooled cooling mixture was added with ruthenium K-based) winter nitrosin wax 4·2 gram (16.09 mmol) and stirred at room temperature for 2 hours, and the reaction mixture was poured into diluted 〇11 The solution was extracted with EtOAc. EtOAc (EtOAc)EtOAc. (3) 0(4,5-monohydro-1H-imidazol-2-yl)-5-(ifosin-4-yl)phenyl]amine 〇0 XXI: Η,Ν

15 Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed in 2-amino-4-(ifosin-4-yl)benzonitrile 3.65 g (18.0 mmol), added to the solution of ethylenediamine 20 ml. The mixture was stirred at EtOAc EtOAc (EtOAc)EtOAc. (4) 8-(morpholine-4-yl)-2,3-dihydroimidazo[i,2-c]oxazolidine hydrochloride 20 〇0

, B" 〇0

-118- The paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (117) in [2-(4,5- 2.60 g (14.6 mmol) of dinitro-1 σ g-yl-2-yl)-5-(ifolin-4-yl)phenyl]amine in a suspension of 2-propanol in 20 ml at 0 ° C 2.32 g of cyanogen bromide (21.9 mmol) was added portionwise and stirred at 10 CTC for 2 hours. After cooling to room temperature, the precipitate was collected and washed with diethyl ether to give the title compound 1. (5) 6-(ethylammonium) nicotinic acid

10 Add 5.00 g of 6-aminonicotinic acid (36.5 mmol) and 3.80 ml of acetic anhydride (40.2 mmol) in a mixture of 30 ml of pyridine at 140 ° C for 24 hours, and add ethyl acetate to the reaction mixture. The mixture was acidified to pH 2 with EtOAc (EtOAc m. (6) 6-(Acetylamino)-N-[8-(morpholine-4-yl)-2,3-dihydroimidazo[1,2-c] σ-quinucin-5-yl Capsule

-119- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm)

200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (1 1 8 in 8-(ifufu-4-yl)-2,3-dihydro-salt [1,2-(: 4嗤4-5-amine bromate 105.7 mg (0.30 mmol), 6-(acetamido) nicotinic acid 81.1 mg (0.45 mmol) and N,N-diisopropylethyl 0.26 ml (1.50 mmol) of amine in a mixture of 2 ml of N,N-didecylguanamine to 5 PyBOP ((1H-1,2,3-benzotriazol-1-yloxy) (Tripyrrolidin-1-yl) scalp hexafluorophosphate) 234.2 mg (0.45 mmol) and stirred at 90 ° C for 16 hours. After cooling to room temperature, a saturated NaHC 3 solution was added to collect the precipitate. It was washed with water, methanol and diethyl ether to give the title compound 41.1 mg of a white solid, yield 31.6%. 10 Melting point: 228°C Mass Spectrum: 434 In-tube PI3K-L inhibitory activity: C In vitro PI3K-T inhibitory activity: A !H -NMR (500 MHz, DMSO-d6) 5 : 3.22-3.30 (m? 4H)? 3.74 (s? 15 3H), 3.86 (m, 2H), 3.97 (m, 2H), 6.77 (br s, 1H) , 7.60 (m, 1H), 8.07 (m, 1H), 8.32 (m, 1H), 8.95 (br s, 1H), 10.60 (s, 1H). Example 2-4: 6-(Ethylamino)-N-[8-(ifu.lin-4-yl)-2,3-dimur 1^mwa[1,2_c]indole oxazoline -5-yl]nicotine guanamine hydrochloride 20 〇0

Me 120-

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (119) in 6-(ethyl amine)-N- [8-(Mf. Lin-4-yl)-2,3-diodor σ sita[l,2-c]oxazoline-5-yl]nicotinium amide (Example 2-3) 20.0 mg (0.046 mmol), a mixture of 1,4-diazane in 1.5 ml of 1,4-diazane was added at a concentration of 4 eq. of HC1 0.5 ml and stirred at room temperature for 40 minutes. 5 The precipitate was collected and washed with diethyl ether. The title compound was obtained as a yellow solid (yield: 78%). Melting point: 237 ° C Mass: 434

In vitro PI3K-cold inhibition activity: B 10 In vitro PI3K-T inhibitory activity: A iH-NMR (500 MHz, DMSO-d6) 5 : 3.41-3.76 (m, 7H), 3.86 (m, 2H), 4· 10 (m,2H), 7.20 (m,1H),7·39 (m,1H),8·19 (m,1H), 8.45 (m,1H),9·09 (br s,1H),10.86 (s, 1H). Example 2-5: 15 N-(8-hydroxy-2,3-di-n-imidazo[l,2-c]oxazolium-5-yl)nicotinamide

N-(8-Methoxy-2,3-dihydroimidazo[l,2-c]oxazolidine-5-yl)nicotinamide (Example 2-22) 3.50 mg (10.9 mmol) And a suspension of 4.25 g of sodium sulfide (54.5 mmol) in 1-methyl-2-pyrrolidone 10 ml at -121-

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (120) Heating at 160 °C for 4 hours (LC-MS indicates complete consumption of starting materials), cooling the mixture to the chamber The volatile by-product was evaporated and the mixture was partitioned between chloroform and a 0.5 eq. NaOH solution. The aqueous layer was neutralized and the formed precipitate was collected to give the title compound 2.34 g. Melting point: 289 ° C Mass spectrum: 308

PI3K-/3 inhibitory activity in vitro: C In vitro PI3K-r inhibitory activity: B 10 iH-NMR (500 MHz, DMSO-d6) δ : 4.01 (m, 2H), 4.15 (m, 2H), 6.75 (dd , 1H, J=8 Hz, 2 Hz), 6.91 (s, 1H), 7.52 (dd, 1H, J=8 Hz, 5 Hz), 7·75 (d, 1H, J=8 Hz), 8.44 ( d, 1H, J = 8 Hz), 8.73 (dd, 1H, J = 5 Hz, 2 Hz), 9.31 (s, 1H), 10.61 (br s, 1H), 12.24 (br s, 1H). 15 Examples 2-6 N N-{8-indole (l-pyrrolyl)ethoxy]-2,3-dihydroimidazo[l,2-c]oxazolium-5-yl}nicotinamide

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, 20 On, N-(8-hydroxy-2,3-dihydroimidazo[l,2-c]oxazol-5-yl)nicotine-122- paper The scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 ψ 15 V. Description of invention (m amide (example 2-1) 70.0 mg (0.23 mmol), N-(2-bromo-B The base ratio is 47. 6 mg (〇·27 mmol) of P and 26 g (0·91 mmol) of potassium carbonate, and a suspension of 5 ml of Ν-dimethylformamide at 120°. The mixture was heated in a sealed tube for 3 hours, and the reaction mixture was concentrated and partitioned between dichloromethane and water. The organic layer was washed with aq. Mg of gray solid, yield 54%. Melting point: 209 ° C. MS: 401

10 PI3K-Wan inhibitory activity in vitro: B In vitro PI3K-T inhibitory activity: B 'H-NMR (500 MHz, DMSO-d6) (5: 4.00 (m? 2H)? 4.12 (m? 2H) 4.30 (s ,4H),6·00 (m,2H),6·84 (m,2H),6·85 (dd,1H,J=6

Hz, 2 Hz), 7.27 (d, 1H, J = 2 Hz), 7.52 (dd, 1H, J = 6 Hz), 7·76 (d, 1H, J = 8 Hz), 8.44 (dd, 1H, J=8 Hz, 2 Hz), 8.72 (dd, 1H, J=5 Hz, 2 Hz), 9·31 (s, 1H), 12.32 (s, 1H). The compounds of Examples 2-7 to 2*»368 were synthesized according to a similar method to Shells 2-1 to 2-6. Loading

Line III Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -123- This paper scale applies China National Standard (CNS) A4 specification (210 x 297 mm) 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention Description (l22 Table 2

.124- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (123) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

- Head" No. MW MASS mp/°C Bin pi3K-r 2-11 CIH 广人Η ° 〇Λα> Η 451,92 416 294(dec.) A 2-12 Nv pjQ Ο 〇ΛΛ u 390,45 391 199(dec.) B 2-13 390,45 391 209 A 2-14 C,H °Ί, 426,91 391 267(dec.) A 2-15 N—\ ΐΡγ^Ο ° οΛαΛ. Η 3 432 , 49 433 227 B -125- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 __ B7 V. Invention description (124)

No. MW MASS mp/°C in vitro pi3K« r 2-16 NV 广人Η h3c 410,50 411 233(dec.) B 2-17 NV cih h3c N 446,96 411 255(dec.) A 2-18 Person NH 〇^r>-3 h3c^/nn 407,48 408 232 B 2-19 Ν--Λ wO c,H u°"Sq 410,91 376 >300 B -126- This paper size applies China National Standard (CNS) A4 Specification (210x297 mm) 200413379 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Invention Description (l25)

-127- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7

Line This paper size applies to China National Standard (CNS) A4 specification (210x297 mm). Installation 200413379 A7 B7 V. Invention Description (127 No. Structure

MASS

Mp / °C — w inside PI3K- r 2-28

CIH

341,80 306 315

A 2-29

344,38 345 190

A 2-30 h3c Ν-

N NH

CIH cr αι> 380,84 345 295 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -3

310,38 311 182 129- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm). 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 _____ B7 V. Invention description (128)

-130- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 ____B7 V. Invention description (l29) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

9 -3 2-

The paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) -131- 200413379 A7 B7 V. Invention Description 130 W No. Structure

MASS

Mp / °C in vitro PI3K- r 2-40

401 401,26 366 270

A 2-41

• i 367, 26 332 328 Order 2-42

406,67 372, 370 243

Line A I I I !• i Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

B

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (m) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed clothing

-133- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 __ B7 V. Invention description (m)

Example number structure MW MASS mp / °C tube pi3K-r 2-48 Η 3 408,42 409 306-307 A 2-49 N-^ Η 390,40 391 289(dec.) A 2-50 -0i^ XNH C,H H' 々50 H 426,87 391 278(dec.) A 2-51 h,,jC^1nh 〆々x> NH 391,39 392 233(dec.) A 2-52 NV CIH H3C, 〇x^s|^\n<^nh H' 々x> NH 427,85 392 210(dec.) A -134- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention (m) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

• i line I I I I• 1 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (134) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

Example number structure MW MASS mp/°C in vitro pi3K-r 2-57 ch3 0 Xaa, H 3 408,42 409 224 B 2-58 CH- N\ °ΧΧλ C1H CH3 0乂〇人CH3 H 3 444,88 409 279 B 2-59 CH, N\ k" A ) CIH ?xxX CH3 O^Y^NV CH3 401,86 366 257(dec.) B 2-60 person H CHi °^c> H 390,40 391 246 A -136-

• ! i η ι I I I I I I I I I I I !• I This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print A7 ____B7 V. Invention description (l35)

Example structure number 1 MW MASS mp/°C In-tube PI3K-r 2-61 ch3 °, 1 ch3 jry CIH °%;> Η 426,87 391 276 A 2-62 ?Η3 ΤΛ °Ύί^ν> ch3 356 ,41 357 248 B 2-63 CIH ?ΧΛνΛνη CH3 〇^〇Ν Μ 376,81 340 270(dec.) B 2-64 ?Η3 〇, CH, ιΓΎ^) 0^S^VCH3 η3〆368,40 368 236-237 B -137- The paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (136 Old Number Structure

MASS

Mp / °C in vitro pi3K-r 2-65 h3c,

400, 24 402, 400 264

A 2-66

436,70 402, 400

A 2-67

436,70 402, 400 289(dec.) Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Staff Consumer Cooperatives 2-68

351,37 352 228(dec.)

A This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 138- 200413379 A7 B7 V. Invention description (l37) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed clothing

, Structure MW MASS mp / °C k 香内 PI3K- r 2-69 Ν*-Λ CIH 人 Η 387,83 352 275(dec.) B 2-70 〆七又。 Η, Η 3 408,42 408 286(dec.) B 2-71 , shouting αΗ Η 3 444,88 408 270(dec.) B 2-72 〇Λα> Η 390,40 391 210(dec.) A 2 -73 ΝV η // > CIH Ηϊ"Η〆々X> Η_._ 426,87 391 289(dec.) A -139- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 .__B7 V. Invention description (m)

-140- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (i39) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

If ^ MW MASS mp/°C Test PI3K- r A 2-78 /HC,H H3c person j^N person 疒3 h3c/〇415,88 379 230(dec.) 2-79 H, seven person Η 3 422,45 422 >310 B 2-80 ΝV Η〆.丫^CIH H 3 458,91 422 305(dec.) A 2-81 ^°yyfx H3cAfVSjlH <. . ^00 H 404,43 405 202 B 2-82 Ν—Λ h,tVY cih 〇Λα> Η 440,89 405 280(dec.) B -14 Factory paper size applies to China National Standard (CNS) A4 specification ( 210 X 297 mm) 200413379 A7 B7 140 V. Invention Description Example Number Structure

MASS

Mp/°C

In vitro test tube PI3K-T 2-83

CIH

384,80 349 >300 2-84

325,76 326 210

B 2-85

CIH

362,22 327 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 6 8 2·

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -142- 200413379 A7 B7 V. Invention Description (Hi side numbering structure

MASS

Mp/°C

In vitro test tube PI3K-T 2-87

370,21 372 228 2-88

CIH

406,67 372, 370 316 CIH 2-89

445,71 411, 409 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 2-90

305,34 306 210

A -143-

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (142) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-144- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (H3 WW number

W

MASS

Mp/°C in vitro PI3K- r 2-95

317,35 318 196-198 2-96

353,81 318 275-277

B Binding 2-97

393,84 358 298-299 Line Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Clothing 2-98

362,22 327 249 This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) -145- 200413379 Α7 Β7 V. Invention description (Μ4 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

-146- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm). 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 ____B7 V. Invention description (M5)

JS and 'MW MASS mp/°C test* PI3K-r 2-103 CIH α 03⁄4 362,22 326 >280 B 2-104 Cl 0 XaAh3 H 3 382,81 383 >280 B 2-105 N— ^\ irV^ σΗ Cl 0乂丫, N 〇Xaa, H 3 419,27 383 > 280 A 2-106 aH recognition >1H c,°%:> H 401,26 365 >280 B -147 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 ___B7 V. Invention description (H6)

-148- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (l47 number structure

MASS

Mp / °C in vitro PI3K- r 2-111

395,77 360 263

A 2-112

Η •i 398,35 399

A order 2-113

434,81 399 270

Line A I I I I• i Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 2-114

321,34 322 110

A This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 149- 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

200413379 A7 B7 V. Description of Invention (149) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 A7 B7 V. Description of invention (150 example structure

MASS

Mp/°C in vitro PI3K- r 2-123

372,82 337 296

A 2-124

360,38 361 287

A 2-125

396 396,84 361 238

A Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Clothes 2-126

386,42 183-184

A This paper size applies _ National Standard (CNS) A4 specification (210 x 297 mm) -152- 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 ___B7 V. Invention description (m)

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 V. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 B7 invention description (l52)

-154- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing five A7 B7 invention description (l53)

-155- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 A7 V Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing B7 invention description (l54)

-156- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 5. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing invention description (l55)

-157- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (l56 Example No. Structure

MASS

Ip/°C in vitro PI3K- r 2-145

OH 420,35 307 229(dec·) 2-146

361,41 362 219(dec.)

B 2-147

305,34 306 195- 196

A Ministry of Economic Affairs Intellectual Property Bureau I·Working Consumer Cooperative Printed

3 H c This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (l57 Example No. Structure:

MW

MASS

Mp/°C in vitro tube POK-r 2-148

CH, 341, 80 306 310 (dec.)

A 2-149

NH 2 306,33 307 •300

A 2-150

NH 342,79 307 290 (dec.)

A • I 4 ά• i Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 2

-159- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (l58 example number structure

MW

MASS

Mp / °C in vitro PI3K- r 2-152 2-153 2-154 2-155

384,83 Η

H

.CH0 320,36 356,82 349 320 320 312 (dec.) 196-197 300(dec.)

A

B

B

H

Cl • 160- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 362,22 326 324 (dec.)

200413379 A7 B7 V. INSTRUCTIONS (159) -161- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Co., Ltd. 200413379 A7 B7 V. Description of Invention (160) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (161) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-163- The paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (l62) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-164- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention (l63) Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

-165- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (l64 Example Number Structure

MW

MASS

Mp / °C in vitro PI3K- r 2-176

CIH

446,82 410 248-249 2-177

342,36 342

275(dec.) B 2-178 N-

N NH 〇Λί> 296,35 297 187-188

B Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (l65 Example No. Structure

MW

MASS

Mp/°C in vitro PI3K- r 2-180

330,80 330 198-199 2-181

C1H

367,26 330 298(dec.) N-

CIH 2-182 Ν ΝΗ

H3C 346,84 310 >250 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (166) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-168- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (l67) Example No. Structure

MW

iMASS

Ip/°C in vitro PI3K-r 2-188

CIH

333,80 306(dec.) 2-189

325,39 326 243 (dec.) 2-190

CIH

HX 361,86 326 289 - 290

A Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 2-

322,37 322 207-208 169-

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of invention ((6) Example number structure

MW

MASS

Mp/°C in vitro PI3K- γ 2-192

358,83 322 271-272 2-193

280,29 281 265 (dec.) Β Η 2-194

Η 316,75 281 309-310 Printed by the Consumers’ Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 V. Invention Description (l69) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

Example number structure MW MASS mp / °C In-tube PI3K-r 2-196 c,h 〇Λ〇436,90 401 239 B 2-197 Η〇^〇^ΰ^ΛΝΗ 351,37 352 210-215(dec. B 2-198 NV c,h ηο-^〇Λ^ΛνΛνη Q 387,83 352 249(dec.) B 2-199 N—\ HO八^^〇人,^人州〇xo 365,39 366 127 A 2-200 N-\ C1H 〇Λ〇401,86 366 243(dec.) B -171- •Installation •Line • This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 V. Description of Invention (170) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

Example number, structure ivrw MASS mp / °C PI3K-r 2-201 HO VIII, human Η D 395,42 396 181 B 2-202 Ν—\ rr^ σΗ 〇x〇431,88 396 229(dec. B 2-203 C,H 0'N 'NH 0 〇Λο 401,81 366 231 (dec.) B 2-204 NV ^人IjiH 406,40 407 265-269(dec.) B 2-205 〇Λο 456,94 421 243-247(dec.) B -172- •Installation•Line· This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (m) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

Example No. Structure MW MASS mp / °C In-vitro pi3K-r 2-206 -丫, 乂人 ◦ Aq 364,37 365 296 B 2-207 . 434,46 435 232-236(dec.) B 2-208 NV 0八^广丫人Ν' C!H, person into N person Η r . ^〇470,92 435 227 B 2-209 N-V 〇Γ^Τ^ϊ夕 c,HO^o °^]Q 530,98 495 247 A 2-210 NV H〇丫丫V u 307,31 308 >300 B -173- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (m) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-174- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm). 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 B7 V. Invention description (173)

-175- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (174) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-176- This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 200413379 A7 B7 V. Description of invention (175) This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

Printed by the Qizhi Intellectual Property Bureau Staff Consumer Cooperatives 200413379 A7 B7 V. Invention Description (176) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-178- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 V Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing B7 invention description (l77)

-179- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (178) -180- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm)

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 200413379 A7 B7 V. Invention description (179 instance number structure

MW

MASS

Mp/°C

In vitro test tube PI3K-T 2-238

, CH 3 CH0 386,84 351 274 (dec.) 2-239

350,38 351 330 (dec.)

D Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (180) -182- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

Example Description 1 Structure ivrvv MASS mp / °C Test #内PI3K-r 2-242 C Ν-Λ /Q c,h N NH h3c/〇400,87 365 321 (dec.) D 2-243 0 Λ> 〇Aas.〇, 336,42 337 169-170 D 2-244 NV Entry 372,88 337 292 (dec.) D 2-245 °%/ 368,42 369 278 (dec.) D Ministry of Economic Affairs Intellectual Property Office Employee Consumption Cooperative Printed 200413379 A7 B7 V. Invention Description (1S1) -183- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

Example No. Structure MW MASS mp / °C In-vitro PI3K-r 2-246. ~. (//, CH3 404,88 369 320 (dec.) D 2-247 oS, 369,40 370 278 (dec.) C 2-248 Ν—Λ 广Ν^' QH 〇/', νη2 405,87 370 308 (dec.) C 2-249 a5L °U/ 〇//, νη2 403,85 403 240 (dec.) D Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 200413379 A7 B7 V. Invention Description (l82 Case No. Real editing, structure '

MW

MASS

In vitro test tube PI3K-T

Ip/°C

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (l83) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

Example number structure L MW MASS mp/°C In-vitro Pi3K-r 2-254 N\ OCa N NH 335,32 334 279-281 D 2-255 449,35 336 .265 (dec.) D 2-256 CN 429 ,36 316 248-250 D 2-257 α$υ 419,37 306 175 (dec.) D 2-258 ο^^0^ν,〇Η3 333,40 334 188-190 D -185- This paper size applies China National Standard (CNS) A4 Specification (210x297 mm) 200413379 A7 B7 V. Invention Description (184) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Example Number Structure MW MASS mp/°C In-vitro PI3K-T 2-259 N\ CIH CH3 °^1〇Γ, 3 369,86 334 266 (dec.) D 2-260 α£Η 447,42 334 240 (dec.) D 2-261 οόί 388,48 389 218-222 D 2-262 οόΐ Ϋ; 461,40 348 253(dec.) D 2-263 oi 〇Aar〇ch3 347,38 348 208-210 D -186- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 A7 B7 V. Description of invention (l85) -187- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

Example number structure 1. ινπν MASS mp / °C In-tube PI3K- r 2-264 〇5: ch3 383,84 348 304 (dec.) D 2-265 ]Γ\ CH3 广丫H3C\/CH3 Η °γ ° 〇λιγ7νη 405,46 406 280 (dec.) D 2-266 ΝΗ 355,40 356 218-220 D 2-267 Ν—V (ΡΥ^Μ) 〇,Η 〇Λα〇391,86 356 309 (dec .) D Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 200413379 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Invention Description (186)

Example number structure MW MASS mp/°C in vitro PI3K-T 2-268 person Η A 〇L ^Cn 356,39 357 267 (dec.) D 2-269 〇 CI person CIH n 392,85 357 324 (dec. ) D 2-270 Ν—'V 4 〇L 356,39 357 209-211 D 2-271 O^Zr 〇Λαϋ 392,85 357 319 (dec.) D -188- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (l87)

Example number structure MW MASS mp / °C In-tube PI3K- r 2-272 recognize '"ΝΗ 〇348,36 349 224-226 D 2-273 〇348,36 349 253-255 D 2-274 Η 0 八Ch3 o^"ct^ch3 434,46 435 289 (dec.) D 2-275 N\ .丨 H. Person (^Γ^°Α〇Η3 470,92 435 282 D -189- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (l88 Example No. Structure

MW

MASS

Mp / °C

In vitro test tube PI3K-T 2-276

291,31 292 204 - 205 2-277

405,34 292

206 (dec.) C 2-278

291,31 292 224 - 225

C Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 2-279

405,34 292 2310(dec.) This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 190- 200413379 A7 B7 V. Invention Description (l89 Example No. Structure

MW

MASS

Mp/°C in vitro PI3K-r 2-280

359,31 360 219-220

D 2-281

395,77 360 -250 2-282

N 334,38 335 249 (dec.)

D Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed nich -191-

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (l9〇) Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

CH

V.CH

-192-

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 Five Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing B7 invention description (m)

-193- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm). 200413379 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 B7 V. Invention description (192)

-194- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (l93 Example No. Structure

MASS

Mp / °C in vitro pi3K-r 2-295

420,35 307 231 (dec.) c 2-296

293,33 294

128 - 129 C Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

-195-

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 invention description (l94) Five Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-196- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (195) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-197- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (196) -198- This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm)

SS : Structure ivrw MASS mp/°C In-tube PI3K-r 2-307 JT) 〇^>rN,, X/ 298,33 299 219 (dec.) c 2-308 〇5: 〇Λαν- Η 380, 84 345 344 (dec.) B 2-309 Ν—\ η3〇^ 440,43 441 250-253 D 2-310 Η〇ν^<! CCah S f 445,36 332 252 (dec.) B Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 200413379 A7 B7 V. Invention description (197) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-199- • I i ordering!! This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (m) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-200- ·; 4·! This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (1" Example Number Structure

MASS

Mp / °C in vitro PDK: r 2-319

N

S

N

374,43 375 260-261

D 2-320

CIH N NH

S

410,89 375 310 (dec.)

D 2-321

374,43 375 281 (dec.)

D Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-201-

This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (200 Example No. 2-324 2-325 2-326 2- 327 2-328 Structure i\rw

MASS

Mp/°C in vitro PI3K-r

〇< CH,

CH.

-202- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 310,38 320,35 228,26 242,28 256,31 311 321 229 243 257 122-123 149-150 189 Amorphous 121 -122

D

D

D

D

D

200413379 A7 B7 V. Description of the invention (2〇l instance number structure

MW

MASS

Ip/°C in vitro PI3K:j 2-329

270,34 271 154 (dec.)

D 2-330

CH, 256, 31 257 104-105

D 2-331

270,34 271 135-136

D Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (2〇2) -204- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

Example number structure MW MASS mp / °C PI3K-r 2-333 c A> C person N NH FF 332,23 333 210-211 D 2-334 N\ °^v 254,29 255 164- 165 D 2-335 0 JO \人N NH 296,38 297 170-172 D 2-336 JT\ 人H〇WCH3 J 1 Bu ch3 ch3 397,48 398 Amorphous D Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 200413379 Economy Ministry of Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (2〇3)

Example number structure MW MASS mp/°C In-vitro PI3K- γ 2-337 Η〇丫 0 431,50 432 119-120 D 2-338 Ν—\ 0 CH Seven dogs: 3 397,48 398 147- 148 D 2-339 ΐΛ ΝΗ 297,36 298 179-180 D 2-340 Ϊ^-3 397,48 398 Amorphous D -205- The paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Description of the invention (2〇4 Example number structure

MW

MASS

Mp/°C in vitro PI3K-r 2-341

431,50 432

D

Y 2-342

350,38 351 Amorphous 2-343

288,31 289 240-241

D Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

-206- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm). 1 I I I I ! I I I ! I I·: 200413379 A7 B7 V. Description of invention (2〇5 Example No. Structure

MW

MASS

Ip/°C in vitro PI3K-r C 3 Η

2-346

N NH 339,42 340 272

D 2-347

376,42 377 244

D 2-348

381,46 382 124

D Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 2-349

Charge IIIIIIIII, ά IIII• i 364,35 365 226 -207- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 Five Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed invention description ( 2〇6

-208- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm). Line 200413379 A7 B7 V. Invention description (207) -209- This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 PCT)

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Co., Ltd. 200413379 A7 B7 V. Description of Invention (208) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

-210- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (2〇9) Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention Description (2W) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -212-

Vi structure [vrw MASS mp / °C in vitro PI3K-J 2-366 N ^\ Chiral 1 1 CIH U 341,80 306 270(dec.) D 2-367 N\ 〇~^ 〇乂Y^NV OH 428 ,88 398 273-274 A 2-368 jr\ χΥχ HCI 〇Me O^V^NV OH 403,83 368 240(dec.) A This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (2U) Example 3-1: (Ζ)-2-σ米唾和[1,2-c]17奎唾°林-5-基-1 -(2-喧-) vinyl alcohol (1) 2-(1Η-imidazol-2-yl)aniline

2-(4,5-Dihydro-1Η-imidazol-2-yl)aniline bromide (50.0 mg, 10 0.207 mmol) and manganese dioxide (170 mg, 1.96 mmol) in Ν, Ν A mixture of '-dimethylpropylurea (2.0 ml) was heated at 150 ° C (bath temperature). After 1 hour, the reaction mixture was cooled to room temperature and poured with hydroxylamine hydrochloride (0.5 g). The resulting mixture was extracted with EtOAc (EtOAc) (EtOAc) Grinding, the precipitate was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (EtOAc, ethyl acetate) -2-yl) aniline (20 mg, 60% yield). 20 (2) 3-keto-3-(2-thienyl)propionic acid ethyl ester

OH

-213-

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (212) in 2-thiophenecarboxylic acid (6.48 g, 50.57 mmol) To a suspension of tetrahydrofuran (100 ml) at 5 ° C, 1, 1, carbonyl diimidazole (8.61 g, 53.09 mmol) was added portionwise, and the mixture was allowed to warm to room temperature and stirred for 5 hours. The reaction mixture was added to a suspension of magnesium chloride (4.86 g, 51.07 mmol) and 3-ethoxy-3-ketopropanoic acid clock (12.91 g, 75.85 mmol) in tetrahydrofuran (50 mL). After stirring at °C for 2 hours, it was stirred at room temperature overnight. The reaction mixture was poured into water, and ethyl acetate was evaporated, and the mixture was washed with brine, dried with sulphuric acid magnesium sulfate, filtered and concentrated under reduced pressure Purification on silica gel by column chromatography (ethyl acetate / hexanes / 15 / 85) Yellow oil. (3) (Z)-2-imidazo[l,2-c]oxazoline-5-yl-1-(2-thienyl)vinyl alcohol 15 ηQ; η 20 2-(1Η-imidazole- 2-yl)aniline (60.0 mg, 0.38 mmol), 3-keto-3-(2-thienyl)propionic acid ethyl ester (74·7 mg, 0.38 mmol) and p-toluenesulfonic acid A mixture of hydrate (36.1 mg, 0.19 mmol) in toluene (30 ml) was heated under reflux for 2 h and cooled to room temperature - 214-

CH, CT

This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200413379 A7 __ B7 V. Inventive Note (213), the reaction mixture is poured into a saturated aqueous solution of NaHC〇3, and the resulting mixture is used. The mixture was extracted with EtOAc (EtOAc). /1) Purification gave 5 (Z)-2-imidazo[Uc]oxazol-5-yl-1-(2-thienyl)vinyl alcohol (37.0 mg, 33% yield) as a yellow powder. Melting point: 128 ° C Mass spectrometry: 294 In vitro PI3K-call inhibition activity:

10 Intra-tube Π3Κ-τ inhibitory activity: D 'H-NMR (300 MHz, COCh) 6: 6.11 (1H, s)? 7.16 (1H, dd? J=3.8, 4·9 Hz), 7·34_7·41 (2H,m),7·53-7·60 (3H,m), 7.64 (1H,d,J=1.7 Hz),7·73 (1H,dd,J=ll,3·8 Hz),8 · 34 (1H, dd, J = 0.9, 7.8 Hz), 14.70 (1H, bs). 15 Example 3-2: Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed (Z)-2-Mini-Sal[1,2-c]Indolin-5-yl-1-(2-indolyl) Ethylene Alcohol hydrochloride

(Z)-2-oxazolo[1,2-c]oxazolium-5-yl-1 -(2-thienyl)ethene-215- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 A7 ----- B7 V. Description of the invention (214 alcohol (〇·〇6 g, 〇·〇 7 mmol) Add HC1 to a solution of chloroform (1 ml) A solution of 1,4-dioxane in a concentration of 4 eq. (5 ml) was diluted with hexanes, and the obtained precipitate was collected by filtration, washed with diethyl ether and dried under reduced pressure to give (?). And carbazole--5- 5 -1-(2-thenyl)vinyl alcohol hydrochloride (0.07 g, quantitative) of a yellow solid. Melting point: 263 ° C (decomposition) Mass spectrum: 294 In-tube PI3K-/ 3 inhibitory activity:

10 Intracellular Π3Κ-7 inhibitory activity: D]H-NMR (300 MHz, DMSO-d6) (5: 6.79 (1H, s)? 7.28 (1H? dd? 15 J=3.8, 4·9 Hz), 7 ·45 (1H, t, J = 7.0 Hz), 7.66-7.77 (2H, m) 5 7·82 (1H, d, J = 1.7 Hz), 7.91 (1H, dd, J=ll, 5.0 Hz), 8·17 (1H dd, J=ll, 3.8 Hz), 8.30 (1H, dd, J=1.0, 8.0 Hz), 8.62 (1H, d, J=1.7 Hz), 14.36 (1H, br). Example 4 -1 : N-isoxazo[1,2-c]oxazoline-5- nicotinic acid decylamine (1) imipo[1,2-c]. 奎 嘴嘴-5-amine economic ministry wisdom Property Bureau employee consumption cooperative printing

20 Β " ill

N in 2-(lH-imidazol-2-yl)aniline (〇·〇6g, 〇·38mmol) in methanol-216- This paper scale applies Chinese National Standard (CNS) A4 specification (210x297 public 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printing 5, Invention Description (2i5) (3 ml) solution was added cyanogen bromide (0.05 g, 0.45 mmol), and the resulting mixture was stirred at room temperature. After overnight, the reaction mixture was poured into water, and the obtained precipitate was collected by filtration, washed with acetone, and dried under reduced pressure to give imidazo[l,2-c]oxazolin-5-amine bromate (0.06 g) , 61% yield) 5 white solids. (2) N-imidazo[l,2-c]oxazolium-5-ylnicotinium amide OH 0

In the imidazo[l,2-c]oxazolium-5-amine bromate (93 mg, 0.35 mmol) and nicotinic acid (124 mg, 1.01 mmol) and DMF (2.5 mM 15 liters) The mixture was added to the mixture at room temperature. Sodium-1 -yl-lactyl-indole-0-pyridyl-sodium hexafluorophosphate (525 mg, 1.01 mmol) and N,N-diisopropylethylamine (0.264 mL, 1.51 mmol) The mixture was stirred at 80 ° C for 6 hours, and after cooling to room temperature, the reaction mixture was poured into a saturated aqueous solution of NaHC 3 , filtered, and the obtained precipitates were collected and washed with acetone under reduced pressure. After drying, N-imidazo[l,2-c]oxazolium-5-ylnicotinate decylamine (40 mg, 39% yield) was obtained as a white solid. Melting point: 223-224 ° C (decomposition) Mass spectrometry: 290 In vitro PI3K-/3 inhibitory activity: -217-

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 V. Invention description (2i6)

试管3Κ-τ^π activity in the test tube: C !H-NMR (300 MHz5 DMSO-d6) 5 : 7.53-7.62 (3H? m)5 7.70 (1H, t, J=7.34 Hz), 8.00 (1H, d , J=8.10 Hz), 8.30 (1H, d, J=7.91 Hz), 8.44 (1H, s), 8.63 (1H, d, J=7.72 Hz), 8·81 (1H, 5 dd) , J = 1.5, 4.7 Hz), 9·49 (1H, s), 13.49 (1H, br). Example 4-2: N-Imidazo[l,2-c]oxazoline-5-Nicotine Indoleamine Hydrochloride

• ii is added to the solution of N-mid and [l,2-c]a quinoid-5-based St-amine (40 mg, 15 0.14 mmol) in methanol (20 mL) in 1 4 eq. of 4-dioxane (0.5 ml), the mixture was concentrated under reduced pressure, and the obtained precipitate was collected by filtration and dried under reduced pressure to give N-imidazole [l, 2-c] Oxazoline-5- nicotinic acid guanamine hydrochloride (40 mg, quant.) as a white solid. 20 Melting point: 228 ° C (decomposition) Mass spectrometry: 290 In vitro PI3K-/S inhibitory activity:

In vitro PI3K-T inhibitory activity: C ^-NMR (300 MHz, DMSO-d6) (5: 7.60 (2H? br) 5 7.65 (1H? t5 -218- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) it ·! Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing clothing 200413379 A7 B7 V. Invention description (2Π) J=7.5 Ηζ), 7·82 (1Η, dd, J=7.3, 8·1 Ηζ), 7.92 (1Η, s), 8.02 (1Η, dd, J=5.5, 7·9 Ηζ), 8.54 (1Η, d, J=8.3 Ηζ), 8.73 (1Η, s), 9.02 (1H, dd, J = 1.3, 5.3 Hz), 9.07 (1H, d, J = 7.53 Hz), 9.67 (1H, s). 5 References [1] Wymaim MP, Sozzani S, Altruda F, Mantovani A, Hirsch E: Lipids on the move: phosphoinositide 3-kinases in leukoc^e function. Immunol. Today 2000; 6: 260-264.

[2] Stein RC, Waterfield MD: PI3-kinase inhibition: a target for drag development? Mol. Med. Today. 2000; 6: 347-357.

[3] Sean A. Weaver, Stephen G. Ward: Phosphoinositide 3-kinases in the gut: a link between inflammation and cancer? Trends in Molecular Medicine 2001; 7: 455-462.

[4] Vanhaesebroeck B, Leevers SJ, Panayotou G., Waterfield MD: Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem. Sci. 1997; 22: 267-272. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative [5] Fniman DA, Meyers RE, Cantley LC: Phosphoinositide kinases. Aimu. Rev. Biochem. 1998; 67: 481-507. -219- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (2i〇[6] Wymann MP, Pirola L: Structure and function of phosphoinositide 3-kinases. Biochim. Biophys. Acta 1998; 1436: 127-150. [7] Sotsios Y, Ward SG: Phosphoinositide 3-kinase: a key biochemical signal for cell migration in response to chemokines. Immunol. Rev. 2000; 177: 217-235. [8] Toker A, Cantley LC : Signalling through the lipid products of phosphoino-sitide-3-OH kinase. Nature 1997; 387: 673-676. [9] Stephens LR, Jackson TR, Hawkins PT: Agonist-stimulated synthesis of phosphatidylinositol ( 3,4,5)-trisphosphate: a new intracellular signalling system? Biochim. Biophys. Acta. 1993; 1179: 27-75. [10] Stephens LR, Eguinoa A, Erdjumentbromage H, Lui M, Cooke F, Coadwell J, Smrcka AS, Thelen M, Cadwallader K, Tempst P, Hawkins PT: The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, plOl· Cell 1997; 89: 105-114. [11] Stoyanov B, Volinia S , Hanck T, Rubio I, Loubtchenkov M, Malek D, Stoyanova S, Van-Haesebroeck B, Dhand R, Numberg B, Gierschik P, Seedorf K, Hsuan JJ, Waterfield MD, Wetzker R: Cloning and characterization of a G protein- Activated human phosphoinositide-3 kinase. Science 1995; 269: 690-693. [12] Kxugmann S, Hawkins PT, Pryer N, Braselmann S: Characterizing the interactions between the two subunits of the plOl/pllOgamma phosphoinositide 3-kinase and their role In the activation of this enzyme by G beta gamma subunits. J. Biol. Chem. 1999; 274: 17152-17158. -220-

I I I I \ I I I J \ I I I I I I

I ordering

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperation, social printing five, invention description (219) [13] Sasaki T, Suzuki A, Sasaki J , Penninger JM: Phosphoinositide 3-kinases in immunity: lessons from knockout mice. J. Biochem. 2002; 131: 495-501. [14] Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, Wakeham A, Itie A, Bouchard D, Kozieradzki I, Joza N, Mak TW, Ohashi PS? Suzuki A, Penninger JM: Function of ΡΙ3Κγ in thymocyte development, T cell activation, and neutrophil migration. Science 2000; 287: 1040-1046. [15] Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D: Roles of PLC-beta2 and -beta3 and ΡΙ3Κγ in chemoattractant-mediated signal transduction. Science 2000; 287: 1046 -1049. • 4 [16] Hirsch E, Katanaev VL, Garlanda C, Azzolino O, Pirola L, Silengo L, Sozzani S? Mantovani A, Altruda F, Wymann MP: Central role for G protein-coupled phosphoinositide 3-kinase γ In Inflamm. Science 2000; 287: 1049-1053. 4 [17] Michael A. Crackower, Gravin Y. Oudit, Ivona Kozieradzki, Renu Sarao et line al: Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. 2002; 110: 737-749. • [18] Emilio Hirsch, Omella Bosco et al: Resistance to thromboembolism in ΡΙ3Κγ-deficient mice. The FASEB Journal· 2001; 15: 2019-2021 · [19] Ui M, Okada T , Hazeki K, Hazeki O: Wortmaimin as a unique probe for an intracellular signalling protein, phosphoinositide 3-kinase. Trends Biochem. Sci. 1995; 20: 303-307. -221- This paper scale applies to Chinese National Standard (CNS) A4 Specification (210x297 mm) 200413379 A7 B7 V. Description of invention (22〇) [20] Vlahos CJ, Matter WF, Hui KY5 Brown RF: A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholino)-8- phenyl-4H-l-benzopyran-4-one (LY294002). J. Biol. Chem. 1994; 269: 5241-5248. Ministry of Economic Affairs Intellectual Property Bureau K Consumption Cooperation, Society Printing - 222- This paper scale applies to China Standard (CNS) A4 eligible Regulation (210x297 mm)

Claims (1)

1. Among them, 10 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 x represents 〇15 Han 6 or NH; Y1 represents CR3 or N; y2 two y3 chemical bond represents a single bond or double bond, provided that Y2 II-Y3 When representing a double bond, Υ and Υ3 independently represent CR4 or Ν, and when ¥匕丫3 represents a single bond, γ2 and Υ3 independently represent CRV or NR4; Ζ, ζ, Ζ3, and Ζ4 independently represent CH, cr2* R ; Rl represents an aryl group having 1 to 3 substituents selected from R", and a Cw cycloalkyl group having 1 to 3 substituents selected from Rn, optionally aryl, heteroaryl a base, an oxyaryl group, an aryloxy group, a heteroaryloxy group or a one or more _ group substituted cN6 alkyl group, λ requires a fluorenyl group, an aryl group, a heteroaryl group, a Ci6 alkoxy aryl group, Oxygen, heteroaryloxy or one or more _ group substituted Cl 6 alkoxy, -223 This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297 public love 200413379 A8 B8 C8 --- - D8 VI. Patent application scope or 3 to 15 members single- or di-ring saturated or unsaturated and containing 1 to 3 heteroatoms selected from N, 0 and S and optionally 1 to 3 a heterocyclic ring selected from a substituent of RU, wherein R represents a halogen group, a nitro group, a hydroxyl group, a cyano group, a carboxyl group, an amine group, an N-(CK6 alkyl)amino group, and an N-(hydroxy Cualkyl)amino group. , n,N-di(Cu alkyl)amino, NJCk fluorenyl), N-(indenyl)-N-(Ci.6 alkyl)amine, NJCw alkylsulfonyl)amine , Ν-(carboxy 10 Cl·6 alkylalkyl)amine, N-(Cb6 alkyl)amino, N-[N,N-di(C!·6 alkyl)aminoindenylene] Amine, N-[Ν,Ν·二(Cl-6 alkyl)amino (Cw alkyl) fluorenyl]amine, N-[n,n-di(Cl 6 alkyl)amine c2- 6 alkenyl]amino, aminocarbonyl, N'(ck alkyl)aminocarbonyl, N,N-di(Cw alkyl)aminocarbonyl15, C3·8 cycloalkyl, Ci·6 alkyl sulfide Base, CN6 Institute Foundation, the Ministry of Affordable Economy, Intellectual Property Office, Staff Consumer Cooperative, Printing Lithoate, CN0 Alkyl, N-Arylamine, where the aryl moiety is 1 to 3 as needed a substituent selected from R101, an N-(arylalkyl)amine group wherein the aryl moiety is optionally 1 to 3 substituents selected from R1G1, an arylalkyl ester group wherein 20 parts of the aryl moiety are Include 1 as needed 3 substituents selected from R1G1, optionally substituted with a mono-, di- or tri--yl group, an amine group, an N-(Ci_6 alkyl)amino group or an N,N-di(Cw alkyl)amino group Alkyl, Ci_6 alkoxy group substituted by mono-, di- or tri-halogen, N-(Ci_6 alkyl) sulphate or (aryl) sulfonylamino group, -224 This paper size applies to China Standard (CNS) A4 specification (210X297 mm) 200413379 A8 B8 C8 D8 VI. Patent application scope or 5 to 7 members saturated or unsaturated and containing 1 to 3 heteroatoms selected from strontium, S and N and optionally a ring containing 1 to 3 substituents selected from R1()1, wherein R1()1 represents a halogen group, a thiol group, an amine group, an N-(Ci_6 alkyl)amino group, and N,N-di(CN6) Alkyl)amino, aminocarbonyl, N-(CV6 alkyl)aminocarbonyl, N,N-di(Cualkyl)aminocarbonyl, pyridyl, optionally via cyano or mono-, di- or a tri-halo-substituted Cw alkane 10 group, or optionally a cyano group, a carboxyl group, an amine group, a fluorene-(<^-6 alkyl)amino group, an anthracene, a fluorenyl-di(Cw alkyl)amino group, an amine Alkylcarbonyl, NJCw alkyl)aminocarbonyl, N,N-di(Cw alkyl)aminocarbonyl Or a mono-, di- or 15-tri-halo-substituted Ci -6 alkoxy; R 2 represents a trans group, a halo group, a schlossyl group, a cyano group, an amine group, an N-(Ci_6 alkyl group) amine group, N, N - bis(Ck alkyl)amino group, N-(hydroxy Cw alkyl)amino group, N-(hydroxyCN6alkylalkyl)amino group, Cu decyloxy group, amine Cw decyloxy group, C2_6 alkenyl group, Aryl, 5 to 7 member 20 saturated or unsaturated and containing 1 to 3 heteroatoms selected from the group consisting of hydrazine, S and N and optionally via a hydroxyl group, a Cw alkyl group, a CN6 alkoxy group, a ketone group, an amine group, Amine CN6 alkyl, NJCk alkyl)amine, N,N-di(Cw alkyl)amine, fluorene-((6-yl)amino, alkyl) phenyl, phenyl, benzene Base C^6 burning base, rebel base, Ci_6 -225 This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) • I i is ordered by Qin Dynasty!! Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 200413379 Αδ Β8 C8 _ D8_ t, patent application range alkyl ester group, aminocarbonyl group, NJ Cu alkyl) aminocarbonyl group or heterocyclic ring of N,N-di(Cw alkyl)amino substituent, -C(0)-R20 Wherein 5 R2() represents Ci_6 alkyl, CN6 alkoxy, Base, NJCw alkyl)amino, N,N-di(Cualkyl)amine, Ν-((^_6醯)amino, or 5 to 7 members saturated or unsaturated and containing 1 to 3 From heteroatoms including 0, S and N and optionally via Ck, Ci_6 alkoxy, keto, amine, N-(Ci_6 alkyl) 10 amine, N,N-di(Ci_6 alkyl) An amine group, a fluorene-(<^_6-yl)-amino group, a phenyl group or a substituted heterocyclic ring, a C-alkyl group substituted by R21 or a Cw alkoxy group optionally substituted by R21, 15 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed R stands for gas-based, early-, di- or di-halo, per group, amine group, Ν-((^_6 alkyl)amine group, N,N-di ( Cw alkyl)amino group, N-(hydroxy Cw alkyl)amino group, N-(halophenyl Cw alkyl)amino group, amine C2_6 alkenyl group, Cw alkoxy group, hydroxy Cw alkane 20 oxy group, -C(〇)-R2()1, -NHC(0)_R2G1, 03_8 cycloalkyl, isodecyl, quinone imido, 2-keto-1,3-oxazolidinyl, aryl Or 5 or 6 members are saturated or unsaturated and contain 1 to 4 heteroatoms selected from the group consisting of 0, S and N and optionally, via a base, a Ci_6 alkyl group, a Ci_6 alkoxy group, a Ci_ 6 Burning vinegar, so -226 This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Α8 Β8 C8 D8 t, patent pending range Cu alkoxy, sulfhydryl, amine, amine Ci_6 An alkyl group, an N-(Cn6 alkyl)amino group, an N,N-di(CN6 alkyl)amino group, an N-((^-6-yl)amino group or a benzyl-substituted heterocyclic ring, wherein 5 R2() 1 represents a hydroxyl group, an amine group, an N-(CN6 alkyl)amino group, an N,N-di(Cw alkyl)amino group, an N-(halophenyl Cu alkyl)amino group, a Ci-6 alkyl group, an amine group. Ci_6 alkyl, amine C2-6, Cw alkoxy, 5 or 6 members saturated or unsaturated and containing 1 to 4 heteroatoms selected from 0, S and N and optionally 10 Ci_6 alkyl, Ci_6 alkoxy, CBu 6 alkyl ester, hydroxy Cu alkoxy, keto, amine, Ν-〇^_6 alkyl) amine, hydrazine, Ν-bis(Cw alkyl)amine a N-(Ci_6 fluorenyl)amino group or an octyl-substituted heterocyclic ring; R3 represents a hydrogen, a halogen group, an aminocarbonyl group, or an aryl group Cw 15 alkoxy group or a mono-, di- or tri-- a halogen-substituted Ci alkyl group; R4 represents hydrogen or Cw alkyl; R5 represents hydrogen or Cu alkyl; and R6 represents Halo, Cw alkyl or hydrogen. 2. A thiazolidine derivative of the formula (I) according to claim 1 of the formula (I), a tautomeric or stereoisomeric form thereof, or a salt thereof, wherein X represents CR5R6 or NH; Y1 represents CR3 Or N; the chemical bond between Y2 and Y3 represents a single bond or a double bond, provided that when Y2=Y3 represents a double bond, -227 ·; 订·! Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed this paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A8 B8 C8 D8 VI. Patent application scope γ2 and γ3 independently represent CR4 or N, and when Y2 two Y3 represents a single bond, γ2 and γ3 independently represent CR3R4 NR4 Z, Z' Z and Z4 independently represent CH, cr2 or N; 5 R represents, if desired, mono-, di- or tri-halo, stupyl, methoxyphenyl, phenoxy or thiol Substituting c!_6 alkyl, optionally substituted by a mono-, di- or tri-halo, phenyl, methoxyphenyl, phenoxy or thiol group, or 10 From the following carbocyclic and heterocyclic rings: cyclopropyl, cyclohexyl, hexamethylene, hexahydropyridinium, pyridinyl, pyridinium , furyl, thiol, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, isoimidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 12,4 -thiadiazolyl, iota, 2,5-thiadiazolyl, 15 oxime, 3,4 thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl , Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperatives, printed clothing I2,5·dioxadiyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,5-triazole Base, hydrazine, 3,4-triazolyl, phenyl, pyridyl, pyridinyl, pyrimidinyl, hydrazine, 1-benzophenylthio, benzothiazolyl, benzimidazolyl, 3H-imidazole And [4,5-b]pyridyl, benzo-20triazolyl, fluorenyl, oxazolyl, imidazo[l,2-a]pyridyl, quinolinyl and 1,8-naphthoquinone a bite group, wherein the carbocyclic ring and the heterocyclic ring are optionally selected from the Chinese national standard (CNS) by one to three selected from the group consisting of a hydroxyl group, a halogen group, a nitro group, a cyano group, a carboxyl group, an amine group, and an alkyl group. )A4 specification (210x297 public) 200413379 Α8 Β8 C8 D8 々, patent pending range, N,N-di(Cw alkyl)amine group, Ν-( 0^6 fluorenyl)amino group, N-(Ci_6) S-amino group, Ν-(曱-)-N-(Ci-6 alkyl)amine group, N-[N,N-di( Cw alkyl)aminomethylene]amino, N-[N,N-di(CN6 alkyl)amino (Cw alkyl)methylene]amino, N-[N,N-5 (Cw alkyl)amino C2_6 alkenyl]amino group, Cw alkylthio group, Cw alkyl group, amine sulfhydryl group, Ci-6 alkoxy group, Ci calcination group. It is more than 17 bases, σ-milyl, σ-saltyl, and 吼17. Substituted by a substituent of a sigma group, a phenyl Ci_6 alkyl ester group, a thiol group substituted with a pyridyl group as needed, 10 a hexahydropyrylene group substituted with a Cu alkyl group or a Ci_6 alkoxy group, and A Cl-6 alkyl group substituted with an early-, di- or di-halogen group is required, and R2 represents a hydroxyl group, a halogen group, a nitro group, a cyano group, a carboxyl group, an amine group, and an N-(CN6 15 alkyl)amino group. , N-(hydroxy Cw alkyl)amino group, N,N-di(Cu alkyl)amino group, N-(hydroxy Cw alkylalkyl)amino group, C2-6 thin group, Ci-6 alkyl ester group, Amino group, Ci -6 methoxy group, amine C 1 _6 ethoxy group, fluorenyl group, ruthenium group, phenyl group, hexahydro fluorenyl group, aryl group, 20 Cw decylamino group as needed Substituted pyrrolidinyl group, optionally substituted by a thiol group, a Ci_6 alkyl group, a thiol group, an aminocarbyl group, an N-(CN6 alkyl)aminocarbonyl group or an N,N-di(Cualkyl)aminocarbonyl group Hexahydropyridinyl group, hexanitrogen substituted by C 1 _6 alkyl group 1:7 to 17 wells, -229 This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) ·; i IIII ·: Ministry of Economic Affairs Intellectual Property Bureau employees Co-operatives printed 200413379 A8 B8 C8 D8 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed γ, the scope of patent application is nitrogen-based, mono-, di- or di-halogen, per group, amine, NJCw alkyl as needed Amine, Ν-(hydroxyCN6 alkyl)amino, hydrazine, fluorenyl-di(Cualkyl)amine, C3-6 cycloalkyl, tetrazolyl, tetrahydropyranyl, fenofyl, oxime Amino, 2-keto-1,3-oxazolidinium 5-yl, phenyl-substituted Cw alkyl, _C(0)-R201, pyrrolidinyl substituted by Cw decylamino group, if necessary, a hexahydroindenyl group per group, a Ci_6 alkyl group, a thiol group, an amino group, an N-(CN6 alkyl)aminocarbonyl group or an N,N-di(Cw alkyl)aminocarbonyl group, or a hexahydropyridinyl group substituted with a Ci_6 alkyl group, wherein R 2 () 1 represents a hydroxyl group, an amine group, an N-CCk alkyl group), an N,N-di 15 (Ci_6 alkyl) amine group, N- (halo nucleus) amine group, Ci_6 alkyl group, Ci-6 alkoxy group, tetrazolyl group, tetrahydropyranyl group, morpholinyl group, pyrrolidinyl group optionally substituted by CN6 mercaptoamine group, if necessary By hydroxyl group, Cu alkyl group, carboxyl group, aminocarbonyl group N-(C^alkyl)aminocarbonyl or N,N-di(Cw alkyl)aminocarbonyl is taken from a 20-hydrogen hexahydrofluoride or, if desired, a Ci-6 alkyl substituted hexahydropyrrole, According to the need of gas base, early -, di- or di-halogen, Luo! Base, Cl -6 alkoxy, hydroxy Ci_6 alkoxy, amine, N-(CU6 alkyl)amine -230 This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) AB c D Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 200413379 s, patent pending range, N,N-di(CN6 alkyl)amine, pyrrolyl, tetrazolyl, tetrahydropyranyl, oxime a pyridyl group, a 2-keto-1,3-oxazolidinyl group, a phenyl group, a -C(0)-R2G1 substituted Ci_6 alkoxy group, a pyridyl group substituted with a Cu sulfhydryl group Pyridyl, 5 hexahydropyridyl substituted by hydroxyl, Cu alkyl, carboxyl, aminocarbonyl, N-(C^alkyl)aminocarbonyl or N,N-di(Cualkyl)aminocarbonyl as desired a hexahydropyridinyl group substituted by a CN6 alkyl group, 10 wherein R2G1 represents a hydroxyl group, an amine group, an N-(Cn6 alkyl)amino group, and an N,N-di(Ci-6 alkyl)amino group. , N-(haloindolyl)amino, Ci_6 alkyl, 6 alkoxy, amino C2_6 alkenyl, tetrazolyl, tetrahydropyranyl, morpholinyl, 15 thiolamino group as needed a substituted pyrrolidinyl group, optionally substituted with a hydroxy group, a Cw alkyl group, a carboxyl group, an aminocarbonyl group, an N-(C^alkyl)aminocarbonyl group or an N,N-di(Cw alkyl)aminocarbonyl group.吼σ定基, or 20 as needed Substituted hexahydropyrrole; R3 represents hydrogen, i group, optionally substituted by aminocarbonyl, aryl Cw alkoxy or early-, di- or di-ifi group, and R4 represents hydrogen or Cw Alkyl; R5 stands for hydrogen or Cu alkyl; and -231 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 10 15 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed Clothes 20 Patent application, R stands for hydrogen, halo or alkyl. 1 According to the scope of the patent application, class i, its tautomer or stereoisomer X derivative or NH; isomer is opened, or its salt, wherein γ1 represents N; Υ2 and γ3 represent Cr3r4; the chemical bond between γ2 and γ3 represents a single bond; Ζ4 represents CH; Ζι, ζ2 and Ζ3 independently represent CH, cr24N; R represents the single--bucket,-up# early, one- or two-^ a C16 alkyl group substituted with a phenyl group, a phenyl group, a phenoxy group, a phenoxy group or a thiol group, optionally substituted by a phenyl group, a phenoxy group, a fluorenyl group or a mono-, di- or tri-functional group. a Cw alkoxy group, or one of them selected from the group consisting of a carbocyclic ring and a heterocyclic ring: cyclopropyl, cyclopentyl, cyclohexyl, hexahydropyridyl, hexahydropyridinyl, pyrrolyl, pyrazolyl, furyl , thiol, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, is imidazolyl, pyrazolyl, 1,2,3-thiadiazolyl, iota, 2,4-thiazide Diazolyl, iota, 2,5-thiadiazolyl, 1,3,4-indenyldithio, i,2,3-g disalyl, u + n-di-salyl, 1,2,5 - hydrazine, i, 3,4-oxadiazolyl, i, 2, 3-tri. Sitrate, 1,2,5-triazolyl, 1,3,4-triazolyl, phenyl, pyridyl, well, pyrimidinyl, hydrazine, 1-phenylenethione, benzothiazole Base, benzimidazolyl, 3Η-imidazo[4,5-b]pyridyl, benzene-232 This paper scale applies to China National Standard (CNS) A4 specification (210 X297 mm) • I 4 set 200413379 Α8 Β8 C8 D8 Sixth, the scope of application for patents and triterpenoids, sulfhydryl, sulfhydryl, imipenone [1,2-a] U than sulfhydryl, σ quinacyl and 1,8 - 吼 吼 定 ,, The carbocyclic ring and the heterocyclic ring are optionally selected from 1 to 3, including a hydroxyl group, a halogen 5 group, a nitro group, a chaotic group, a thio group, an amine group, an N-(Ci_6 alkyl)amino group, and an N-(hydroxy Ci-6 alkyl group). Amino, N,N-di(Cu alkyl)amino, N-(Ci-6 fluorenyl)amino, alkyl ester) amine, N-(indenyl)-NJCk alkyl) amine, N,N-di(CN6 alkyl)amino C2_6 alkenyl)amino, Ν-((6-6)sulfonylamino, N-[N,N-10 bis(Cw alkyl)amine Methylene]amino group, Cw alkylthio group, Cw alkyl fluorenyl group, amine-based base, Ci-6 alkoxy group, Ci-6-sodium group, pyrrolyl group, imidazolyl group Substituted by pyrazolyl, pyrrolidinyl, pyridyl, phenyl C 1 -6, or substituted by pyridyl, if desired, substituted by Ci_6 alkyl or Cw alkoxy Hydrogen pyridinyl, and Ck substituted by mono-, di- or tri-i groups as needed:): Completed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, R2, halogen, nitro, cyanide Amino group, amine group, N-(Ci_6 leu) 20 amine group, N,N-di(Ci_6 alkyl)amino group, group Ci-6 alkyl group) ** alkyl) amine group, C2-6 alkenyl group, Ci_6 alkane Ester group, aminocarbonyl group, thiol group, hexanitrogen. Ratio of σ-based, moffolinyl, phenyl, optionally substituted with pyridyl group of NJCw fluorenylamine or Ν-((^-6 alkyl)carbonylamino group, -233 This paper scale applies to Chinese national standards ( CNS)A4 Specification (210x297 mm) 200413379 A8 B8 C8 D8 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed Clothes VI. The scope of application for patents is hydroxy substituted hexahydropyridyl, if necessary, via Cw alkyl, phenyl a Cw alkyl group, a Cw alkyl ester group or an amine ruthenium carbon group substituted hexanitrozide ratio σ well base, if necessary, via an amine group, a gas group, a C 1 -6 burnt group, a ruthenium group, or a 5-mono- Ci-6 alkyl group substituted with a di- or tri--yl group, which does not require a base group, a gas group, a thiol group, a C 1-6 alkoxy group, a C 1-6 aryl group, a Cu alkyl ester group, an amine group, or an alkyl group. Amino, NJCk alkyl)aminocarbonyl, N,N-di(Ci-6 alkyl)amine, N,N-di(Ck alkyl)aminocarbonyl, aminocarbonyl, amine Cw alkylcarbonyl 10 Base, N-(halino)amino group, via-Ci-6 alkoxy group, C3-6 cycloalkyl, fenofyl, morpholinylcarbonyl, pyrrolidinyl, pyrrolyl, hexahydropyridine Base Group, or an optionally substituted benzyl group of hexahydro-pyrazolyl group was cultivated; 15 R3 represents hydrogen; R4 represents hydrogen; R5 represents hydrogen; and R6 represents hydrogen. 4. A thiazolidine derivative of the formula (I) according to claim 1 of the formula (I), a tautomeric or stereoisomeric form thereof, or a salt thereof, wherein X represents CR5R6 or NH; Y1 represents N Y2 and Y3 represent CR3R4; the chemical bond between γ2 and γ3 represents a single bond; -234 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A8 B8 C8 D8 VI. Patent application scope Z4 stands for CH; Z1, Z2 and Z3 independently represent N, CH or CR2; R1 stands for cyclopropyl, cyclopentyl, cyclohexyl, 2-furyl, 3-furanyl , σσ siting base, ° dense σ base, tower tillage, hexahydropyrrole, 5 1,2,3-thiadiazolyl, 1,3-benzothiazolyl, morphine, 3Η-imidazole [4,5-b]pyridyl, 1H-pyrrol-2-yl substituted by Ci_6 alkyl, if desired, 1H-pyrrol-3-yl substituted by Ci_6 alkyl, 1 or 2 Cu, if necessary Alkyl-substituted pyrazolyl, 10 isoxazolyl substituted with 1 or 2 Cw alkyl groups, if desired, 2-thiol substituted by chlorine, nitro, cyano or Cw alkyl, optionally 3-Thienyl substituted by chlorine, nitro, cyano or Cu alkyl, 15 hexahydropyridyl substituted by Cw alkyl ester or benzyl ester, printed by the Ministry of Economic Affairs, Intellectual Property Office, Consumer Cooperatives It is required to be 1 to 3 selected from the group consisting of fluorine, chlorine, hydroxyl, nitro, gas group, Wei group, Ci_6 alkyl group, Ci_6oxy group, acetal group, amine group, Ν-((6-6 alkyl)amine Base, N-CCk fluorenyl) amine group, N-(Ci-6 alkane Esteryl)amino, N,N-di(CN6 alkyl)amino, N-(methylindolyl)alkyl, Cu alkylthio, Ci-6 alkylsulfonyl, sulfonamide, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, and a phenyl group substituted with a substituent of a hexahydropyrylene group substituted with a C 6 alkyl group, optionally 1 or 2 selected from the group consisting of chlorine, a hydroxyl group, a carboxyl group, and Cw-235. This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Α8 Β8 C8 D8 VI. Apply for patent dry alkoxy, Cu alkylthio, amine, NJCw alkyl) amine, N-( Hydroxy CN6 alkyl)amino, N,N-di(Cw alkyl)amine, N-(Ck-decyl)amine, Ν-((6-6 alkyl)sulfonylamino, N-[N , N-di(Cw alkyl)aminomethylene]amino group and, if necessary, a pyridyl group substituted with a substituent of a Cw alkyl group of 5 generations, optionally substituted with a Ci_6 alkyl group , if desired, 1 or 2 1,3-thiazolyl groups selected from the group consisting of Cw alkyl, pyridyl and N-(Cu alkyl ester) amine groups, optionally substituted with Ci_6 alkyl group, 10 Take Ci_6 alkyl or trihalo Ci_6 alkyl as needed Benzomidyl, 1,2,3-benzotriazolyl substituted by Cw alkyl, if desired, substituted by a trihalo-substituted Ci.6 alkyl substituted 1,8-naphthalene Pyridyl, 15 Ci_6 alkyl substituted by tri-i, phenyl, phenoxy or thiol, or printed by the Ministry of Economic Affairs, Intellectual Property Office, Consumers' Cooperative, as required by phenyl, phenoxy or thiophene a substituted alkoxy group; 20 R2 represents a fluorine, chlorine, bromine, a hydroxyl group, a nitro group, a vinyl group, a cyano group, an amine group, an amino ethoxy group, an NJCk alkyl group, an amine group, and an N, N-di (C!_ 6 alkyl)amino, N-(hydroxy Cualkylalkyl)amine, fluorenyl, hexahydropyridinyl, fenofyl, phenyl, optionally substituted with acetamino group Pyrolizine, -236 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A8 B8 C8 D8 t, the scope of patent application is determined by the carboxy group substituted hexahydrogen ratio σ base, as needed a hexahydroquinone σ well group substituted with a methyl group, a nictyl group, a C 1 _6-ester or an amino group, optionally via a cyano group, a tri-fluoro group, a thiol group, or a fluorene group. An amine-based 5-, 3-butyl ester, tetrahydropyranyl or morpholinyl-substituted C ι 6 alkyl group, optionally per group, murine group, methoxy group, methyl group, and second group Amino group, carboxyl group, aminoethyl group, dimethylamino group, aminocarbonyl group, decylaminocarbonyl group, dimethylaminocarbonyl group, isopropylaminocarbonyl group, fluorobenzyl group 10 amino group, cyclopropyl group, σ Specific ratio of 0 °, hexahydropurine sigma, tetrahydro σ-pyranyl, phenanthrene 11-based, phenanthroline-based, 2-keto-1,3-oxazolidinyl, 酞醯Amine-fluorenyl- or hydroxy-Cw alkenyloxy substituted Cw alkoxy, R3 represents hydrogen; 15 R4 represents hydrogen; R5 represents hydrogen; and R6 represents hydrogen. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives 5. According to the scope of the patent application, the azole pyrimidine derivative, its tautomer or stereoisomeric form, or a salt thereof, 20 X represents CR5R6 or NH; Y1 represents N; Y2 and Y3 represent CR3R4; chemical bond between Y2 and Y3 represents a single bond; Z3 and Z4 represent CH; -237 This paper scale applies to China National Standard (CNS) A4 specification (210x297) 200413379 A8 B8 C8 D8 t, the patent scope Z1 and Z2 independently represent CH or CR2; R1 represents cyclopropyl, cyclopentyl, cyclohexyl, 2-furyl, 3-furyl, imidazolyl, 1H -pyrrol-2-yl, 1H-pyrrol-3-yl, pyrimidinyl, hydrazine, hexahydropyrrole, 1,2,3-thiadiazolyl, 1,3-benzene 5-thiazolyl, hydrazine a phenyl group, a 3H-imidazo[4,5-b]pyridinyl group, a pyrrolyl group substituted with a Cu alkyl group, if necessary, a pyrazolyl group substituted with 1 or 2 Cw alkyl groups, optionally 1 or 2 Cw alkyl-substituted iso-4-oxazolyl, 2-thiol 10 groups optionally substituted by chlorine, nitro, cyano or CN6 alkyl, optionally via chlorine, nitro, cyano or C I- 6 alkyl substituted 3-thiol, hexahydropyridyl substituted by Cu alkyl ester or benzyl ester, if necessary, 1 to 3 selected from the group consisting of fluorine, chlorine, hydroxyl, nitro, 15 cyanide Base, Weiji, Ci_6 base, Ci_6 alkoxy, Ci_6 burnt ester base, Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed amine, NXCk alkyl) amine, ISKCk sulfhydryl), N-(Cw Alkyl)amino, N,N-di(Cw alkyl)amine, N-(decylalkyl)amine, Cw alkylthio, Cu alkylsulfonyl, amidoxime, pyrrole a phenyl group substituted with a substituent of a hexahydropyrylene group substituted with a Ci-6 alkyl group, if necessary, 1 or 2 selected from the group consisting of chlorine, a hydroxyl group, a carboxyl group, and a Cw alkoxy group. Base, Cu alkylthio, amine, NJCu alkyl) amine, N-(hydroxy Cw alkyl) amine, N, N-di(Cw alkyl) amine, N-238 National Standard (CNS) A4 Specification (210 X 297 mm) 200413379 Α8 Β8 C8 D8 \, Patent Application (Cu 醯) Amino, Ν-((^·6 alkyl)sulfonylamino, N- [N,N-two (Ci _6 burning base) a pyridyl group substituted with a substituent of a Ci-6 alkyl group substituted with a trihalo group, optionally a pyridyl group substituted with a Cm alkyl group, 5 optionally including 1 or 2 Cu alkyl, pyridyl and N-(C^alkyl ester)amino substituted 1,3-thiazolyl, optionally substituted by Cw alkyl, optionally via Ci_6 alkyl or trihalo Ci_6 a pyridyl-substituted benzoxanthene group, a 1,2,3-benzotriazolyl group substituted with a Ci_6 alkyl group as required, and optionally substituted with a Cu-alkyl group substituted by a tridentate group as needed , 8-naphthalene 17 is more than a butyl group, optionally substituted by a trihalo group, a phenyl group, a phenoxy group or a thiol group, or 15 is optionally substituted with a phenyl group, a phenoxy group or a thiol group. Cb6 alkoxy; R2 represents fluorine, chlorine, bromine, hydroxy, nitro, vinyl, cyano, amine, aminoethoxycarbonyl, Ν-((^_6 alkyl)amine, N, N -2 (C^ Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed 6 alkyl) Amino, N-(hydroxy C^6 alkylalkyl)amine 20, 2-furyl, hexahydropyridyl, IF Olinyl, phenyl, acetonitrile as needed Amino-substituted pyrrolidinyl group, optionally substituted by hydroxy group, hexahydropyridyl group, if desired, substituted by mercapto, benzyl, Cw alkyl ester or amine carbonyl, hexahydrogen ratio σ well base, -239 paper The scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 200413379 A8 B8 C8 D8 VI. The scope of application for patents depends on the needs of cyano, tri-fluoro, sulfhydryl, decyl ester, amino group, a Ci-6 alkyl group substituted with a tributyl sulfonium group, a tetraazainium sulphide group or a ruthenium group, or a hydroxy group, a cyano group, a methoxy group, a methyl ester group, a tert-butyl ester group, a fluorenyl group, or Aminoethyl hydrazide, dimethylamino, amino group, guanylaminocarbonyl, dimethylaminocarbonyl, isopropylaminocarbonyl, fluorobenzylaminocarbonyl, cyclopropyl, pyrrolidinyl, hexahydropyridine Base, tetrahydroσ-pyranyl, ruthenium sulphate, ruthenium sulphonylamino, 2-keto-1,3-indole-10-oxazolidinyl, quinoneimine-fluorenyl or hydroxy Ci_6 olefin The oxy-substituted Ci-6 alkoxy group, R3 represents hydrogen; R4 represents hydrogen; R5 represents hydrogen; and 15R6 represents hydrogen. 6. The fused azole pyrimidine derivative, its tautomer or stereoisomeric form, or a salt thereof according to the formula (I) of claim 1, wherein X represents CR5R6 or NH; Bureau employee consumption cooperative printed Y1 for N; 20 Y2 and Y3 for CR3R4; Y2 and Y3 represent chemical bonds; Z1 and Z4 represent CH; Z2 and Z3 independently represent CH or CR2; R1 represents cyclopropyl, Cyclopentyl, cyclohexyl, 2-furyl, 3-furan-240 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A8 B8 C8 D8 \, patent pending range, imidazolyl, 1H Pyrrole-2-yl, 1H-pyrrol-3-yl, pyrimidinyl, column. Well base, hexahydrotetramine: σ well base, 1,2,3-σ stopper dimercapto, 1,3-benzothiazolyl, porphyrinyl, 3Η-imidazo[4,5-b]pyridyl, If necessary, pyridinyl substituted by Ci_6 alkyl group, 5 pyrazolyl substituted by 1 or 2 Cu alkyl groups, if necessary, 1 or 2 Cu alkyl substituted isoxazolyl, if necessary, by chlorine 2 - σ 嗯 取代, substituted by chloro, thiol, murine or C 1 -6 alkyl, if necessary, via Cw An alkyl ester group or a benzyl ester group substituted hexahydropyridyl group, optionally containing 1 to 3, including fluorine, chlorine, hydroxyl, nitro, cyano, weigen, Ci-6 alkyl, Ci-6 alkoxy, Ci_6^ S, amino, NJCk alkyl)amino, NKCk fluorenyl), N-15 (C alkyl) amine, N,N-di(Cw alkyl)amine, N-( The Department of Intellectual Property of the Ministry of Economic Affairs, the Intellectual Property Bureau, the Consumer Cooperatives, the printing base) alkyl)amine, Ci_6 alkylthio, Cu alkylsulfonyl, sulfonyl, pyrrolyl, imidazolyl, pyrazolyl and, if necessary, C 1 -6 alkyl substituted hexaazinium 1:7 substituted by a substituent of the phenyl group, 2 0, if necessary, 1 or 2 selected from the group consisting of chlorine, hydroxyl, carboxyl, Ci-6 alkoxy, Cw alkylthio, amine, Ν-γκ alkyl) amine, N-(hydroxy Cw alkyl)amine, Ν, Ν-bis(Cw alkyl)amino, Ν-(Ci_6 fluorenyl)amine, NJCk alkyl)sulfonylamino, N-[N,N-di(CU6 alkyl)amino-based Amino group and, if necessary, three-unit-based -241 paper size applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Α8 Β8 C8 D8 t, the patent application scope replaced by CN6 alkyl substituent Pyridyl group, ton σ well group substituted by C 1 -6 alkyl group, if necessary, substituted by 1 or 2 amine groups including Cw alkyl, pyridyl and Ν-(<^-6 alkyl) groups a 1,3-thiazolyl group, optionally substituted with a Cu 5 alkyl group, optionally substituted with a Cu alkyl group or a trihalo C 1 -6 alkyl group, if desired, via a Ci_6 alkane Substituted 1,2,3-benzotriazolyl, 1,8-naphthoquinone sigma, optionally substituted by a trihalo-substituted Cu alkyl group, 10 as desired, via trihalo, phenyl , phenoxy or thiol-substituted Cl-6 a Ci_6 alkoxy group substituted by a phenyl group, a phenoxy group or a thiol group; 15 R- represents a fluorine, a chlorine, a desert, a thiol group, a thiol group, a vinyl group, a cyano group, an amine group, an amine group Ethyloxy, alkyl)amino, N,N-di(Ci-6 alkyl)amine, N-(hydroxy Cw alkyl VNKCw alkyl)amine, 2-17-fanyl, hexa-nitrogen Sigma-based, morphine-based, phenyl, the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperative, prints the pyrrolidinyl group, which is substituted with an acetamino group, and the hexahydropyridyl group, which is optionally substituted with a hydroxy group, if necessary. A hexahydroquinone σ well group substituted with a benzyl group, a benzyl group, a CV6 alkyl ester group or an amine carbonyl group, optionally containing a cyano group, a tri-fluoro group, a carboxyl group, an oxime ester group, an aminocarbonyl group, a third butyl group, and a fourth group. Nitrogen σ is more than sulfanyl or morphine sylylene substituted -242 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Α8 Β8 C8 D8 f, the scope of application for Ci_6 burning base, or as needed Hair group, gas group, decyloxy group, decyl ester group, tributyl sulfonate group, carboxyl group, aminoethyl group, dimethylamino group, aminocarbonyl group A 5-aminocarbonyl, dimethylaminocarbonyl, isopropylaminocarbonyl, fluorobenzylaminocarbonyl, cyclopropyl, pyrrolidinyl, hexahydropyridyl, tetrahydropyranyl, fenoflavinyl, oxime a silylamino group, a 2-keto-1,3-oxazolidinyl group, a quinone imine group or a hydroxy Cw alkenyloxy group substituted with Ci-6 alkoxy group, 10 R3 represents hydrogen; R4 represents hydrogen; R5 represents Hydrogen; and R6 represents hydrogen. The azole pyrimidine derivative of the formula (I), the interconverted 15 isomer or stereoisomeric form thereof, or a salt thereof, wherein X represents CR5R6 or NH; Y1 represents N; Y2 and Y3 represent CR3R4; the chemical bond between the Y2 and Y3 printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs represents a single bond; 20 Z3 and Z4 represent CH; Z1 and Z2 independently represent CH or CR2; R1 represents 3H-imidazole a [4,5-b]pyridyl group, optionally substituted with a hydroxy group, an amine group, an ethenyl group, a methoxybenzyloxy group or a methylsulfonylamino group, is substituted with a benzoheptyl hydrazine base σ group, 243 This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 Α8 Β8 C8 D8 VI. Scope of patent application or 1,3-thiazolyl substituted by 1 or 2 thiol groups if necessary; R2 represents fluorine , chlorine, bromine, ruthenium, hexahydropyrrole, methyl hexafluoro-port ratio σ well, methyl, trifluoromethyl, or 5, if necessary, via, cyano, wei, dimethyl Amino group, tetrahydroσ-pyranyl, fenofyl, morphine, fluorenyl, fluorenyl, orthoquinone _6 alkoxy, R3 represents hydrogen; R4 represents hydrogen; 10 R5 represents hydrogen; and R6 represents hydrogen. 8. A fused azole pyrimidine derivative, a tautomer or stereoisomeric form thereof, or a salt thereof according to the formula (I) of claim 1, wherein X represents CR5R6 or NH; 15 Y1 represents N Y2 and Y3 represent CR3R4; the chemical bond between Y2 and Y3 represents a single bond; Z1, Z3 and Z4 represent CH; the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints Z2 for CR2; 20 R1 stands for 3H-imidazo[4, 5-b]pyridyl, if desired, substituted with a hydroxy, amine, acetoamine, methoxybenzyloxy or methylsulfonylamino group, a benzoindole 4 σ group, or as needed 1 or 2 thiol-substituted 1,3-thiazolyl groups; -244 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A8 B8 C8 D8 Patent application scope ίο 15 Ministry of Economic Affairs Intellectual Property Office employees The consumer cooperative prints 20 R for fluorine, gas, desert, morphine, hexammine σ, fluorenyl hexahydropyridinyl, methyl, trifluoromethyl, or optionally hydroxy, cyano, Carboxyl, dimethylaminocarbonyl, tetrahydropyranyl, fenofyl, ruthenium sulphate, sulphate The base or g is indigo blue, the imido group is substituted with Ci_6 alkoxy, R3 represents hydrogen; R4 represents hydrogen; represents hydrogen; and R6 represents hydrogen. 9. The fused azole pyrimidine derivative, the tautomer or stereoisomeric form thereof, or a salt thereof according to the formula (I) of claim 1, wherein the derivative is selected from the group consisting of the following compounds: N-(7,8-monomethoxy-2,3-dihydromethane hydrazino[l,2-c]. quinine sulphin-5-yl) for the determination of decylamine; 2-(7,8 -monomethoxy-2,3-dihydromylon sitting and [l,2_c]. Kui 坐 sit u-linylpyridin-3-ylvinyl alcohol; Ν-(7,8-monodecyloxy-2, 3-Dihydro- 米 吐 [ [1,2-(:] 啥 啥 咐-5-yl)- 1 Η-benzimidazol-5-decylamine; 6-(acetamido)-Ν-(7, 8-dimethoxy-2-,3-dihydroimidazo[^+ quinazolin-5-yl)nicotinium amide; Ν- {5-[2-(7,8-didecyloxy-2) , 3-dinitrogen. Rice saliva [1,2-(:]. Kudolin 11 _5 yl)-1-hydroxyvinyl]pyridin-2-yl}acetamide; 2-({5-[ 2-hydroxy-2-acridin-3-ylvinyl]-7-decyloxy-2,3-dihydromipropion [1,2-cp-purine. Lin-8-yl}oxy)- N,N-Dimethyletheneamine; 245 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) ·! 4 Order 200413379 A8 B8 C8 VI. Patent application scope '" ' --- ~ A {{tetrahydro-2Η·_^ylmethoxy) n-face [1,2 exocarbazole oxime]]κ3·yl vinyl alcohol; 2-[8-(2, ethoxy group) 7_Methoxy group dihydrogen(tetra) and (10) quinazoline-5-yl; μι_pyridine_3_yl vinyl alcohol; 5 (|5·(四)基如比-3_基乙县]_7_甲Oxygen-based succinyl[l,2-c]oxazolyl-8-yl}oxy)acetic acid; 4-({5-[2'-baser-3-ylvinylmethoxy-- 2,3_dihydroimidazo[l,2-c]carbazole oximeyl}oxy)butyric acid; , ({5-[2, base such as 唆-3-ylvinylmethoxy-2 , 3_dihydrooxazole 10 and U,2-c]oxazoline-8-yl}oxy)acetonitrile; 2-[7-methoxy-8-(2H-tetrazol-5-ylmethoxy) -2,3-dihydroimidazo[l,2-c]indole-5-yl]_1.pyridinyl-3-ylvinyl alcohol; 2-[7-decyloxy-8_(4 - 咁福咁_4-yl-4·ketobutoxy)_2,3, dioxin and [l,2-c]oxazolidine-5-yl]-l-σ-pyridin-3_ Vinyl alcohol; 15 5_[Buhydroxy-2-(8-moff-4-yl-2,3-dihydroimidazo[llc]carbazole. Lin-5-yl) ethylene group]σ ratio σ -3--3-ol; Ν-(2,3-dihydroimidazo[i,2-c]carbazole _5_yl)-hydroxy-nicotinamide; 6-(Acetylamino)-N-(7,9-dimethoxy-8-methyl-2,3-dihydroimidazo[20,2-c]喳Oxazolin-5-yl)nicotinium amide; N-(8,9-dimethoxy-2,3-dihydroimidazo[l,2-c]carbazole. Lin-5_yl)-5_ hydroxynicotinate guanamine; 5-carbyl-N-(7-methoxy-2,3-dihydromimethodol nicotine amide; -246 paper size applicable to China Standard (CNS) A4 specification (210x297 mm) 200413379 VI. Patent application scope N-(7,8-:foxy-2,3_dihydro, oxazo[(Woxyoctyl)oxy] Amine amine; base) 5 Ν-(7,8·dimethoxy-2,3_dihydromipropion [hydroxy nicotinic acid amide; *] group) 5 5 5-based basal-(trifluoromethyl) Base)_2,3_:hydrogen(tetra) and [yl]nicotine amide; J soil main forest) Ν-{8-[3-(1,3-di-yl-1 3 - and ου window ^ 5 · one 虱-2H_isoindol-2-yl)propoxy]- 2,3-dihydro-flavored saliva and like chlorpheniramine _ base} in the test of decylamine; N (7 / odor _8_methoxy _ 2,3·: Hydrogen imipenyl [1,2_φ 奎 Hungary _5-yl) raise 10 alkali guanamine; ^ ^ knee called methoxy 2,3_ dihydrogen and [1, called Kui Shi 5 - Base) in the presence of amine; H1H-benzoate I-based)·2-(Μ-dimethoxy-2-,3-dihydro-s-[l,2-c]oxazolium-5-yl)ethylene Alcohol; 15 2-(8,9-dimethoxy-2,3-dihydrol-xanthene-yl)-small (2,4-dimethyl-1,3-thiazole-5-yl) ; vinyl alcohol; N-(9-oxime Base-2,3_dihydromipropene [Shan Bukui. Sitting 咐_5 boat see Benzene σ Mow-5 - decylamine; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 N-(8-&gt Odor-2,3-dihydroimidazo[p-cp-carbazole-based]1H•benzimidazole-5-decylamine; N-(8-methoxy-2,3-dihydroimidazo[ i,2-c]oxazolium 咁5_yl)_m-benzopyran-5-bristamine; N-(8-methyl-2,3-hydrogen methane and [l,2-c ]. Kui. Sitting in the forest _5_ base) benzo 247 This paper scale applies to China National Standard (CNS) A4 specifications (210x297 mm) 200413379 A8 B8 C8 D8 Patent application range yummy-5-decylamine; 8-(trifluoromethyl) dihydromi-methane and quinone-based base]. benzimidazole-5-decylamine; N-(7-fluoro-2,3-dihydroindole rice saliva [❻小奎如林j基)_m_Benzimidine-5-acid amine; N (7-methoxy oxime 2,3-dihydromipropene [^ Zhongkui. Sitting mouth Lin Qiao _ base) in the test Amine; N-(8' chloro-2,3-di-argon (tetra) and m] 唉 唉 咐 j )). Benzomidin-5-decylamine; ίο 6-(乙胺胺基)_N_(8_? Fushen 4_base_2,3_two scent σ sit and take Yixiaokui σ sitolin-5-yl) nicotine decylamine; 1-(1Η-benzimidazole _5_yl)_2_(8_? Fore _4 2,3_diazoxazo[l,2-c]oxazoline-5-yl)vinyl alcohol; 15 Ν-{5-[1 side base-2|?福喷_4|2,3_ Dihydrogen sulphate and oxazolidine-5-yl)vinyl]σ-pyridyl-2-yl}acetamidamine; 6-mercapto-N-(8-norfos-4-yl-2, 3-dihydro-flavor. Sit and [u-exidazole-5-base) nicotine guanamine; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed benzopyrene I base) _2 κ 曱 曱 hexahydropyridinium σ well Small base dihydroimidazo[l,2-c]carbazole] vinyl alcohol; 2 〇 ( (2,3_ dihydrogen. Meter. Sit and [nc]n Kui, sit, Lin Qian [n pyridine-6-decylamine; 5 N-(7,8-dimethoxy 2,3-dihydroimidazolium oxazolidine-5-yl) a 3-indole-imidazo[4,5-b]pyridin-6-nonylamine; N-[7-(trifluoromethyl)-2,3-dihydro-flavored σ sitting and [by Xiaokui ^林士基η扎 - 248 This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 public) 200413379 AB c D s, patent application range benzimidazole-5-decylamine; N-(7,9-dioxine Base-2,3-dihydroimidazo[l,2-c]oxazoline-5-yl)-1H-benzimidazol-5-decylamine; N-{5-|>(7,9- Dimethoxy-8-methyl-2,3-dihydroimidazo[l,2-c]quinoquinone-5-yl)-1-perylvinyl]σ ratio -2- base} Acetamide; Ν-{5-[2-(7-bromo-9-methyl-2,3-dihydroimidazo[l,2-c]oxazolium-5-yl)-1-hydroxyethene And pyridyl-2-yl}acetamide; and 2-(8,9-dimethoxy-2,3-dihydroimidazo[l,2-c]oxazoline-5-yl)-1 -. ratio. Din-3-yl vinyl alcohol. Ίο 1 〇. A pharmaceutical preparation comprising as an active ingredient a fluorinated pyrimidine derivative, a tautomeric or stereoisomeric form thereof, or a physiologically acceptable salt thereof according to the first aspect of the patent application. 1L An agent according to claim 10 of the patent application, which further comprises one or more pharmaceutically acceptable excipients. The agent according to claim 10, wherein the fused azole pyrimidine derivative, its tautomer or stereoisomeric form, or a physiologically acceptable salt thereof is a PI3K inhibitor. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives. 13. The pharmaceutically acceptable azole pyrimidine derivative, its tautomer or stereoisomeric form, or physiologically acceptable thereof, according to claim 10 of the scope of the patent application. The class of salt 20 is a PI3K-τ inhibitor. 14. An agent according to claim 10 of the patent application for use in the prevention and/or treatment of an inflammatory or immunomodulatory disorder. -249 This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200413379 A8 B8 C8 ----D8 VI. Application for patent scope 15. According to the application of the fourth paragraph of the patent application scope, it is used for Prevention and/or treatment of asthma, rhinitis, allergic diseases, spontaneous immunopathology, rheumatoid arthritis, Graves' disease and atherosclerosis. 16. An agent according to the scope of claim 1 for use in the prevention and/or treatment of 5 neurodegenerative disorders, Alzheimer's disease or localized ischemia. 17. An agent according to claim 14 for use in the prevention and/or treatment of diabetes, cancer, myocardial systolic dysfunction, heart failure, ischemia, pulmonary hypertension, renal failure or cardiac hypertrophy. 18. A medicament for the treatment and/or prevention of inflammation according to the fused nibble bite derivative of claim 1 of the scope of the patent application, its 10 tautomer or stereoisomeric form, or a physiologically acceptable salt thereof Use of sexual disorders or diseases. 19. Slightly based on item 1 of the scope of the patent application. dense. A derivative, a tautomeric or stereoisomeric form thereof, or a physiologically acceptable salt thereof, for use in the treatment and/or prevention of asthma, rhinitis, allergic diseases or spontaneous immunopathology. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumption Cooperative, Printing and Garment 20· According to the scope of the patent application, the fused chelate derivative, its tautomer or stereoisomer form, or its physiologically acceptable salt The manufacture of a medicament for the treatment and/or prevention of diabetes, cancer, myocardial contraction, heart failure, ischemia, pulmonary hypertension, renal failure or cardiac hypertrophy. 21. A medicament for the treatment and/or prevention according to the scope of claim 1 of the fused form of the stagnation derivative, its tautomer or stereoisomeric form, or a physiologically acceptable salt thereof Barriers related to PI3K activity - 250 ^ Zhang scale applicable ^ National Standard (CNS) A4 specification (210χ297 mm) Application for patent or disease. 22. According to the scope of patent application, item i is fused (4). Derivatives | Tautomeric or stereoisomeric forms, or physiologically acceptable agents thereof, for use in the treatment and/or prevention of a field or disease associated with bribery activity. A method for controlling an inflammatory disorder or disease in a human or a mammal, which is effective for inhibiting the compound of the ninth aspect of the patent. And the armor 10 15 24 - a method for controlling an inflammatory disorder or disease in a human or a mammalian material, which is a compound according to the first aspect of the patent application, which is effective for suppressing the amount of ρΐ3Κ1 by administration. 25. A method for controlling asthma, rhinitis, allergic diseases or spontaneous immunopathology in a human or a mammal, which is effective for inhibiting ΡΙ3Κr by administering a compound according to the scope of the patent application. In humans or mammals for controlling diabetes, cancer, myocardial systolic dysfunction, collar failure, ischemia, pulmonary hypertension, renal failure or: dirty hypertrophy, which can effectively inhibit the basis of the ship _ r by medication Apply for a compound of the scope of patent i. 251 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 297 297 mm) (B), the representative symbol of the representative figure is a simple description ·· None 200413379 Chemical formula...:〃 lie , R1, B-i page